RIPK2 inhibitors and method of treating cancer with same

ABSTRACT

The invention is a compound represented by Structural Formula (I): (I); or a pharmaceutically acceptable salt thereof. Values for the variables are provided herein. Also included is a pharmaceutical composition comprising the compound represented by Structural Formula (I) and a pharmaceutically acceptable carrier or diluent and methods of treating a subject with cancer with the compound of Structural Formula (I).

RELATED APPLICATIONS

This application is a U.S. national stage filing under 35 U.S.C. §371(c), of International Application No. PCT/CA2015/051024, filed onOct. 9, 2015, which claims the benefit of U.S. Provisional ApplicationNo. 62/068,985, filed Oct. 27, 2014. The entire teachings of theaforementioned applications are incorporated herein by reference.

BACKGROUND

Receptor-interacting serine/threonine-protein kinase 2 (RIPK2, alsocalled RICK, RIP2, CARDIAK, and CARD3) has been implicated in a varietyof functions including: integrating signals for innate and adaptiveimmune systems, regulating apoptosis, controlling a myogenicdifferentiation checkpoint, and regulating nuclear-factor-kappa-beta(NFkB) and Jun N-terminal kinase (JNK) activation. RIPK2 is composed ofan N-terminal serine/threonine kinase catalytic domain and a C-terminalregion containing a caspase activation and recruitment domain (CARD).

RIPK2 physically interacts with CLARP, a caspase-like molecule known tobind to Fas-associated protein with death domain (FADD) and caspase-8.Expression of RIPK2 promoted the activation of caspase-8 and potentiatedapoptosis induced by Fas ligand, FADD, CLARP, and caspase-8. Deletionmutant analysis revealed that both the kinase domain andcaspase-recruitment domain were required for RIPK2 to promote apoptosis.Significantly, expression of a RIPK2 mutant in which the lysine of theputative ATP-binding site at position 38 was replaced by a methioninefunctioned as an inhibitor of CD95-mediated apoptosis. Thus, RIPK2represents a novel kinase that may regulate apoptosis induced by theCD95/Fas receptor pathway.

Because expression of RIPK2 affects the regulation of apoptosis in avariety of cell types, RIPK2 activity may be an important factor in thedevelopment of disease states in which regulation of apoptosis iscritical. Significantly, RIPK2 protein level is increased in the frontalcortex of patients with Alzheimer's disease (Engidawork et. al., 2001,Biochem. Biophys. Res. Commun. 281: 84-93).

Analysis of RIPK2 deficient mice indicates that RIPK2 is required forregulation of innate and adaptive immune and inflammatory responses.RIPK2 deficient mice were born in the expected Mendelian ratio, andshowed no gross developmental abnormalities or abnormal composition oflymphocytes as determined by flow cytometry (Kobayashi et. al., 2002,Nature 416: 194-199; Chin et. al., 2002, Nature 416: 190-194). However,these mice exhibited a decreased ability to defend against infection bythe intracellular pathogen Listeria monocytogenes (Chin et. al., 2002).RIPK2 deficient macrophages and T-cells showed severely reduced NFkBactivation (Kobayashi et. al., 2002; Chin et. al., 2002). RIPK2deficiency also resulted in impaired interferon-.gamma. production inboth T.sub.H1 and natural killer cells and impaired T.sub.H1-celldifferentiation (Kobayashi et. al., 2002; Chin et. al., 2002). Analysisof RIPK2 deficient mice suggests that RIPK2 is a candidate target forimmune intervention.

RIPK2 has been reported to physically associate with several proteinsinvolved in receptor mediated signaling through the tumor necrosisfactor (TNF) family of receptors including TNFR-1, TNFR-2, Fas(CD-95/APO-1), lyphotoxin-.beta. receptor, CD40, CD30, OX-40, DR3, DR4,and DR5. For example, RIPK2 physically interacts with CLARP, acaspase-related protein that interacts with Caspase-8 and FADD (aprotein which associates with the Fas/CD-95 and TNFR-1 receptors)(Inohara et. al., 1998). CLARP could therefore function as an adaptermolecule to link RIPK2 to proximal components of the receptor signalingcomplex.

RIPK2 also physically interacts with Caspase-1 (Thome et. al., 1998;Humke et. al, 2000, Cell 103: 99-111). This protein interaction ismediated by CARD domains in the C-terminus of RIPK2 and in the prodomainof Caspase-1 (Thome et. al., 1998; Humke et. al., 2000). RIPK2 enhancesthe activation of Caspase-1 by promoting its oligomerization which leadsto processing of adjacent pro-Caspase-1 protein (Humke et. al., 2000).The association between RIPK2 and Caspase-1 can be abrogated by theICEBERG protein, which inhibits and/or displaces RIPK2 by bindingCaspase-1 through its own CARD domain. (Humke et. al., 2000).

RIPK2 has been reported to associate directly with p75 receptor in anerve growth factor (NGF) dependent fashion (Khursigara et. al., 2001)and with several receptor associating proteins including TRAF1, TRAF2,TRAF5, and TRAF6 (Thome et. al., 1998; McCarthy et. al., 1998).Co-expression of CD40 receptor, RIPK2, TRAF1 and TRAF2 resulted inassociation of RIPK2 with CD40 (McCarthy et. al., 1998). Likewise,co-expression of TNFR-1 receptor, RIPK2, TRADD, TRAF1 and TRAF2 resultedin association of RIPK2 with TNFR-1 (McCarthy et. al., 1998).Collectively, these data suggest that RIPK2 is a component of the p75,CD40, Fas/CD-95 and TNFR-1 receptor signaling complexes.

RIPK2 activity appears to be altered by interaction with ligands. Forexample, expression of polypeptides comprising CARD domains with highaffinity for RIPK2 protein binding partners may prevent RIPK2 fromphysically associating with other CARD domain containing proteins (Humkeet. al., 2000). Protein-protein interactions mediated by CARD domainshave also been reported to be disrupted by nitric oxide (NO) (Zech et.al., 2003, Biochem J. 371(Part 3): 1055-64). Compounds that alter theserine-kinase activity of RIPK2 may also influence RIPK2 function.Methods for assessing the kinase activity of RIPK2 have been described(Inohara et. al., 1998; Thome et. al., 1998; McCarthy et. al., 1998;Navas et. al., 1999). Methods for screening for compounds that modulateserine-threonine kinase activity have been disclosed (US2003/0134310A1;WO 02/14542). In addition, anti-sense oligonucleotides designed toinhibit RIPK2 have been described (U.S. Pat. No. 6,426,221 B1).

Because of the multiple therapeutic values of compounds targetingreceptor mediated signaling pathways that modulate apoptosis, cellulardifferentiation, and immune response, and the essential regulatory roleplayed by RIPK2, there is a need in the art for novel compounds that caninhibit RIPK2.

SUMMARY OF THE INVENTION

Applicants have now discovered that certain pyrrolo[3,2-d]pyrimidinecompounds are RIPK2 inhibitors (see Example B). Applicants have also nowdiscovered that these pyrrolo[3,2-d]pyrimidine compounds have potentanticancer activity against breast cancer cells, colon cancer cells, andovarian cancer cells in cell culture study (see Examples C-D); andpotent anti-inflammatory/anti-autoimmune diseases (see Example E). Basedon these discoveries, pyrrolo[3,2-d]pyrimidine compounds, pharmaceuticalcompositions thereof, and methods of treating cancer, autoinflammatorydisease and autoimmune disease with the pyrrolo[3,2-d]pyrimidinecompounds are disclosed herein.

One embodiment of the invention is a compound represented by StructuralFormula (I):

or a pharmaceutically acceptable salt thereof. Values for each of thevariables are provided below.

Another embodiment of the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier or diluent and acompound represented by Structural Formula (I) described above or apharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of treating a subjectwith cancer comprising administering to the subject an effective amountof a compound of Structural Formula (I) or a pharmaceutically acceptablesalt thereof.

Another embodiment of the invention is a method of treating a subjectwith an autoinflammatory disease comprising administering to the subjectan effective amount of a compound of Structural Formula (I) or apharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of treating a subjectwith an autoimmune disease comprising administering to the subject aneffective amount of a compound of Structural Formula (I) or apharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of inhibiting RIPK2activity in a subject in need of inhibition of RIPK2 activity,comprising administering to the subject an effective amount of acompound represented by Structural Formula (I) or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the invention is a compound represented byStructural Formula (I) or a pharmaceutically acceptable salt thereof foruse in therapy. In some embodiments, the therapy is for treating asubject with cancer. In some embodiments, the therapy is for treating asubject with autoinflammatory disease. In some embodiments, the therapyis for treating a subject with autoimmune disease. Alternatively, thetherapy is for inhibiting RIPK2 activity in a subject in need ofinhibition of RIPK2 activity.

Another embodiment of the invention is the use of a compound representedby Structural Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating a subject with cancer.

Another embodiment of the invention is the use of a compound representedby Structural Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating a subject withautoinflammatory disease.

Another embodiment of the invention is the use of a compound representedby Structural Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating a subject withautoimmune disease.

Another embodiment of the invention the use of a compound represented byStructural Formulas (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for inhibiting RIPK2 activity in asubject in need of inhibition of RIPK2 activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating that in vivo response of HCT116xenografts in SCID mice to a treatment for 18 days with compound A3administered at different doses.

FIGS. 2(A)-(C) are graphs illustrating the effects of compound A3 oncytokine production by dendritic cells. FIG. 2(A) shows the results ofmouse bone marrow dendritic cells being stimulated for 24 hours with 0.3ng/ml LPS±1 μg/ml MDP (i.e., NOD2 agonist) in the presence of compoundA3. FIG. 2(B) shows the results of mouse bone marrow dendritic cellsbeing stimulated for 24 hours with 0.3 μg/ml Pam3Cys±1 μg/ml MDP (i.e.,NOD2 agonist) in the presence of compound A3. FIG. 2(C) shows the effectof compound A3 on the percentage of YFP positive cells (Levels of IL-12p70, left panel), and effects on cell viability (TNFα, right panel).

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the invention is directed to a compoundrepresented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Cy is cycloaliphatic, heterocyclyl, aryl, or heteroaryl;

Y is absent, —CR^(b)R^(b)—, —O—, —NR^(b)—, —S(O)_(n)—;

R₁ is cycloaliphatic, heterocyclyl, aryl or heteroaryl, each of which isoptionally substituted with 1 to 3 groups individually represented byR^(a);

R₃ is H, heterocyclyl or heteroaryl optionally substituted with 1 to 3groups selected from —F, —Cl, —Br, I, —CN, —NO₂, —OR^(b), —C₁-C₄alkyl,—(C₁-C₃)alkylene-OR^(b), —(C₁-C₃)alkylene-NR^(b)R^(b), —C₁-C₄haloalkoxy,(C₃-C₈)cycloalkyl, —NR^(b)R^(b), —C(═O)NR^(b)R^(b),—NR^(b)(C═O)NR^(b)R^(b), —S(O)_(n)NR^(b)R^(b), C(═O)OR^(b),—OC(═O)OR^(b), —S(O)—R^(b), —NR^(b)S(O)_(n)R^(b), —C(═S)OR^(b),—O(C═S)R^(b), —NR^(b)C(═O)R^(b), —C(═S)NR^(b)R^(b), —NR^(b)C(═S)R^(b),—NR^(b)(C═O)OR^(b), —O(C═O)NR^(b)R^(b), —NR^(b)(C═S)OR^(b),—O(C═S)NR^(b)R^(b), NR^(b)(C═S)NR^(b)R^(b), —C(═S)R^(b) or —C(═O)R^(b);

each R₄ is independently selected from —F, —Cl, —Br, I, —CN,—NR^(b)R^(b), —OR^(b), —C₁-C₄alkyl, —(C₁-C₃)alkylene-OR^(b),—(C₁-C₃)alkylene-NR^(b)R^(b), —C₁-C₄haloalkyl, or —C₁-C₄haloalkoxy;

each R^(a) is independently selected from —F, —Cl, —Br, I, —CN, OR^(b),—C₁-C₄alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —C₁-C₄haloalkoxy,—(C₁-C₃)alkylene-OR^(b), or —(C₁-C₃)alkylene-NR^(b)R^(b);

each R^(b) is independently —H or —C₁-C₄alkyl;

x is 0, 1, 2, 3, or 4;

each m is independently 0, 1, 2, or 3; and

each n is independently 0, 1, or 2.

In a second embodiment, the invention provides a compound represented bystructural formula (II):

or a pharmaceutically acceptable salt thereof. Values for the variablesin Structural Formulas (II) are as described for Structural Formula (I).

In a third embodiment, the invention provides a compound represented bystructural formula (III):

or a pharmaceutically acceptable salt thereof. Values for the variablesin Structural Formulas (III) are as described for Structural Formula (I)or (II).

In a fourth embodiment, the invention provides a compound represented bystructural formula (I), (II) or (III), wherein R₁ is optionallysubstituted phenyl, optionally substituted cyclopentyl, optionallysubstituted cyclohexyl, optionally substituted thienyl, optionallysubstituted pyridinyl, optionally substituted thiazolyl, optionallysubstituted pyrrolyl, optionally substituted imidazolyl, optionallysubstituted furanyl, optionally substituted oxazolyl, optionallysubstituted isoxazolyl, optionally substituted pyrazolyl, optionallysubstituted isothiazolyl, optionally substituted pyrmidinyl, optionallysubstituted pyrazinyl, optionally substituted pyridazinyl, optionallysubstituted oxadiazolyl, optionally substituted tetrahydropyranyl,optionally substituted triazolyl, or optionally substitutedthiadiazolyl, and values for the remainder of the variables are asdescribed above for Structural Formula (I), (II), or (III).

In a fifth embodiment, the invention provides a compound represented bystructural formula (I), (II) or (III), wherein R₁ is optionallysubstituted phenyl, optionally substituted cyclopentyl, optionallysubstituted thienyl, or optionally substituted tetrahydropyranyl, andvalues for the remainder of the variables are as described above forStructural Formula (I), (II), or (III) or in the fourth embodiment.

In a sixth embodiment, the invention provides a compound represented bystructural formula (I), (II) or (III), wherein R₃ is optionallysubstituted monocylic heterocyclyl or optionally substituted monocylicheteroaryl, and values for the remainder of the variables are asdescribed above for Structural Formula (I), (II), or (III), or in thefourth, fifth embodiment. Alternatively, R₃ is optionally substitutedmonocylic heterocyclyl.

In a seventh embodiment, the invention provides a compound representedby structural formula (I), (II) or (III), wherein m is 0, and values forthe remainder of the variables are as described above for StructuralFormula (I), (II), or (III), or in the fourth, fifth, sixth embodiment.

In an eighth embodiment, the invention provides a compound representedby structural formula (I), (II) or (III), wherein R₃ is optionallysubstituted azetidinyl, optionally substituted morpholinyl, optionallysubstituted piperazinyl, optionally substituted piperidinyl, optionallysubstituted tetrahydropyranyl, optionally substituted pyrrolidinyl,optionally substituted thiomorpholinyl, optionally substitutedtetrahydropyranyl, or optionally substituted tetrahydrofuranyl,optionally substituted homomorpholinyl, optionally substitutedhomopiperazinyl, optionally substituted thiomorpholine dioxide, oroptionally substituted thiomorpholine oxide, and values for theremainder of the variables are as described above for Structural Formula(I), (II), or (III), or in the fourth, fifth, sixth, or seventhembodiment.

In a ninth embodiment, the invention provides a compound represented bystructural formula (I), (II) or (III), wherein R₃ is optionallysubstituted morpholinyl, optionally substituted piperazinyl, optionallysubstituted piperidinyl, or optionally substituted thiomorpholinyl, andvalues for the remainder of the variables are as described above forStructural Formula (I), (II), or (III), or in the fourth, fifth, sixth,seventh, or eighth embodiment.

In a tenth embodiment, the invention provides a compound represented bystructural formula (I), (II) or (III), wherein the compound isrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein R₅ is —C₁-C₄alkylor —(C₁-C₃)alkylene-OR^(b), and values for the remainder of thevariables are as described above for Structural Formula (I), (II), or(III), or in the fourth, fifth, sixth, seventh, eighth or ninthembodiment.

In an eleventh embodiment, the invention provides a compound representedby structural formula (I), (II) or (III), wherein the compound isrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein Y is absent or—CH₂—; and Y is attached to the meta or para position of the phenylring, and values for the remainder of the variables are as describedabove for Structural Formula (I), (II), or (III), or in the fourth,fifth, sixth, seventh, eighth or ninth embodiment.

In a twelfth embodiment, the invention provides a compound representedby structural formula (I), (II) or (III), wherein the compound isrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein R₅ is —H,C₁-C₄alkyl, —(C₁-C₃)alkylene-OR^(b); Y is absent or —CH₂—; and Y isattached to the meta or para position of the phenyl ring, and values forthe remainder of the variables are as described above for StructuralFormula (I), (II), or (III), or in the fourth, fifth, sixth, seventh,eighth or ninth embodiment.

In a thirteenth embodiment, the invention provides a compoundrepresented by structural formula (I), (II) or (III), wherein R₁ is

and values for the remainder of the variables are as described above forStructural Formula (I), (II), or (III), or in the fourth, fifth, sixth,seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.

In a fourteenth embodiment, the invention provides a compoundrepresented by structural formula (I), (II) or (III), wherein each R^(a)is independently selected from —F, —Cl, or —CH₃, and values for theremainder of the variables are as described above for Structural Formula(I), (II), or (III), or in the fourth, fifth, sixth, seventh, eighth,ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

The invention also includes the compounds depicted by structure and/ordescribed by name in the Exemplification. The invention includes boththe neutral form of these compounds as well as pharmaceuticallyacceptable salts thereof. Treatments with and/or uses of these compoundsincludes the neutral form of these compounds as well as pharmaceuticallyacceptable salts thereof.

The term “alkyl” used alone or as part of a larger moiety, such as“alkoxy” or “haloalkyl” and the like, means saturated aliphaticstraight-chain or branched monovalent hydrocarbon radical. Unlessotherwise specified, an alkyl group typically has 1-4 carbon atoms, i.e.(C₁-C₄)alkyl. As used herein, a “(C₁-C₄)alkyl” group is means a radicalhaving from 1 to 4 carbon atoms in a linear or branched arrangement.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom,represented by —O-alkyl. For example, “(C₁-C₄)alkoxy” includes methoxy,ethoxy, propoxy, and butoxy.

The terms “haloalkyl” and “haloalkoxy” means alkyl or alkoxy, as thecase may be, substituted with one or more halogen atoms. The term“halogen” means F, Cl, Br or I. Preferably the halogen in a haloalkyl orhaloalkoxy is F.

“Hydroxyalkyl” is an alkyl group substituted with hydroxy.

“Alkoxyalkyl” is an alkyl group substituted with alkoxy.

An “alkenyl” means branched or straight-chain monovalent hydrocarbonradical containing at least one double bond. Alkenyl may be mono orpolyunsaturated, and may exist in the E or Z configuration. Unlessotherwise specified, an alkenyl group typically has 2-6 carbon atoms,i.e. (C₂-C₆)alkenyl. For example, “(C₂-C₆)alkenyl” means a radicalhaving from 2-6 carbon atoms in a linear or branched arrangement.

“Alkynyl” means branched or straight-chain monovalent hydrocarbonradical containing at least one triple bond. Unless otherwise specified,an alkynyl group typically has 2-6 carbon atoms, i.e. (C₂-C₆)alkynyl.For example, “(C₂-C₆)alkynyl” means a radical having from 2-6 carbonatoms in a linear or branched arrangement.

“Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon radical,typically containing from 3-8 ring carbon atoms, i.e.,(C₃-C₈)cycloalkyl. (C₃-C₈)cycloalkyl includes, but is not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

“Cycloaliphatic” means C₃-C₁₂ monocyclic (C₃-C₈) or multicyclic (C₇-C₁₂,e.g., bicyclic, tricyclic, spirocyclic, etc.) hydrocarbon that iscompletely saturated or has one or more unsaturated bonds but is not anaromatic group, i.e., (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkenyl. Examplesof a cycloaliphatic group are cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl and cyclohexenyl.

The term “aryl group” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, means a carbocyclic aromaticring. It also includes a phenyl ring fused with a cycloalkyl orcycloaliphatic group. The term “aryl” may be used interchangeably withthe terms “aryl ring” “carbocyclic aromatic ring”, “aryl group” and“carbocyclic aromatic group”. An aryl group typically has six tofourteen ring atoms. Examples includes phenyl, naphthyl, anthracenyl,1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl,indenyl and the like. A “substituted aryl group” is substituted at anyone or more substitutable ring atom, which is a ring carbon atom bondedto a hydrogen.

The term “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroarylgroup”, “heteroaromatic ring”, and “heteroaromatic group”, are usedinterchangeably herein. “Heteroaryl” when used alone or as part of alarger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers toaromatic ring groups having five to fourteen ring atoms selected fromcarbon and at least one (typically 1 to 4, more typically 1 or 2)heteroatoms (e.g., oxygen, nitrogen or sulfur). “Heteroaryl” includesmonocyclic rings and polycyclic rings in which a monocyclicheteroaromatic ring is fused to one or more other aromatic orheteroaromatic rings. As such, “5-14 membered heteroaryl” includesmonocyclic, bicyclic or tricyclic ring systems.

Examples of monocyclic 5-6 membered heteroaryl groups include furanyl(e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g.,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g.,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), oxazolyl(e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g.,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl,4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl),thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl,triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl),tetrazolyl (e.g., tetrazolyl), and thienyl (e.g., 2-thienyl, 3-thienyl).Examples of polycyclic aromatic heteroaryl groups include carbazolyl,benzimidazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, indolyl,benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl,indazolyl, isoindolyl, acridinyl, or benzisoxazolyl. A “substitutedheteroaryl group” is substituted at any one or more substitutable ringatom, which is a ring carbon or ring nitrogen atom bonded to a hydrogen.

“Heterocyclyl” means a saturated or unsaturated non-aromatic 4-12membered ring radical optionally containing one or more double bonds. Itcan be monocyclic, bicyclic, tricyclic, spirocyclic, or fused. Theheterocycloalkyl contains 1 to 4 heteroatoms, which may be the same ordifferent, selected from N, O or S. The heterocyclyl ring optionallycontains one or more double bonds and/or is optionally fused with one ormore aromatic rings (e.g., phenyl ring). The term “heterocyclyl” isintended to include all the possible isomeric forms. Examples ofheterocycloalkyl include, but are not limited to, azetidinyl,morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl,dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl,dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.Examples of polycyclic heterocycloalkyl groups include dihydroindolyl,dihydroisoindolyl, dihydrobenzimidazolyl, dihydrobenzothienyl,dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzotriazolyl,dihydrobenzothiazolyl, dihydrobenzoxazolyl, dihydroquinolinyl,tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl,dihydroindazolyl, dihydroacridinyl, tetrahydroacridinyl,dihydrobenzisoxazolyl, chroman, chromene, isochroman and isochromene.

The term “spiro” refers to a cycloaliphatic or heterocyclyl that sharesone ring carbon atom with another cycloaliphatic or heterocyclyl groupin the molecule.

Certain of the compounds described herein may exist in variousstereoisomeric or tautomeric forms. Stereoisomers are compounds whichdiffer only in their spatial arrangement. When a disclosed compound isnamed or depicted by structure without indicating stereochemistry, it isunderstood that the name or structure encompasses all possiblestereoisomers, geometric isomers, including essentially pure stereo orgeometric isomers, as well as combination thereof.

When a geometric isomer is depicted by name or structure, it is to beunderstood that the geometric isomeric purity of the named or depictedgeometric isomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure byweight. Geometric isomeric purity is determined by dividing the weightof the named or depicted geometric isomer in the mixture by the totalweight of all of the geomeric isomers in the mixture.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well-known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

When a compound is designated by a name or structure that indicates asingle enantiomer, unless indicated otherwise, the compound is at least60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as“enantiomerically pure”). Optical purity is the weight in the mixture ofthe named or depicted enantiomer divided by the total weight in themixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted bystructure, and the named or depicted structure encompasses more than onestereoisomer (e.g., as in a diastereomeric pair), it is to be understoodthat one of the encompassed stereoisomers or any mixture of theencompassed stereoisomers are included. It is to be further understoodthat the stereoisomeric purity of the named or depicted stereoisomers atleast 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomericpurity in this case is determined by dividing the total weight in themixture of the stereoisomers encompassed by the name or structure by thetotal weight in the mixture of all of the stereoisomers.

Included in the present teachings are pharmaceutically acceptable saltsof the compounds disclosed herein. The disclosed compounds have basicamine groups and therefore can form pharmaceutically acceptable saltswith pharmaceutically acceptable acid(s). Suitable pharmaceuticallyacceptable acid addition salts of the compounds described herein includesalts of inorganic acids (such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organicacids (such as, benzenesulfonic, benzoic, citric, ethanesulfonic,gluconic, glycolic, isethionic, lactic, lactobionic, methanesulfonic,succinic, and p-toluenesulfonic). Compounds of the present teachingswith acidic groups such as carboxylic acids can form pharmaceuticallyacceptable salts with pharmaceutically acceptable base(s). Suitablepharmaceutically acceptable basic salts include ammonium salts, alkalimetal salts (such as sodium and potassium salts) and alkaline earthmetal salts (such as magnesium and calcium salts). Compounds with aquaternary ammonium group also contain a counteranion such as chloride,bromide, iodide, acetate, perchlorate and the like. Other examples ofsuch salts include hydrochlorides, hydrobromides, sulfates,methanesulfonates, nitrates, citrates, or mixtures thereof includingracemic mixtures], succinates, benzoates and salts with amino acids suchas glutamic acid.

Compounds described herein can inhibit RIPK2. Thus, generally, compoundsdescribed herein are useful in the treatment of diseases or conditionsassociated with such kinases.

In one embodiment, the compounds described herein are RIPK2 inhibitors,and are useful for treating diseases, such as cancer, associated withsuch kinase(s). Alternatively, the compounds described herein are RIPK2inhibitors and are useful for treating diseases associated with RIPK2,such as cancers, autoinflammatory diseases or autoimmune diseases.

Another aspect of the present teachings relates to a method of treatinga subject with cancer comprising administering to the subject aneffective amount of a compound described herein. In one embodiment, thecompounds described herein inhibit the growth of a tumor.

Cancers that can be treated (including reduction in the likelihood ofrecurrence) by the methods of the present teachings include breastcancer, colon cancer, and ovarian cancer. In one embodiment, the canceris selected from leukemia, acute myeloid leukemia, chronic myelogenousleukemia, breast cancer, brain cancer, colon cancer, colorectal cancer,head and neck cancer, hepatocellular carcinoma, lung adenocarcinoma,metastatic melanoma, pancreatic cancer, prostate cancer, ovarian cancerand renal cancer. In one embodiment, the cancer is lung cancer, coloncancer, brain cancer, neuroblastoma, prostate cancer, melanoma,glioblastoma multiforme or ovarian cancer. In another embodiment, thecancer is lung cancer, breast cancer, colon cancer, brain cancer,neuroblastoma, prostate cancer, melanoma, glioblastoma multiforme orovarian cancer. In yet another embodiment, the cancer is breast cancer,colon cancer and lung cancer. In another embodiment, the cancer is abreast cancer.

In yet another embodiment, the cancer is a basal sub-type breast canceror a luminal B sub-type breast cancer. In yet another embodiment, thecancer is a basal sub-type breast cancer. In yet another embodiment, thebasal sub-type breast cancer is ER (estrogen receptor), HER2 and PR(progesterone receptor) negative breast cancer. In yet anotherembodiment, the cancer is a soft tissue cancer. A “soft tissue cancer”is an art-recognized term that encompasses tumors derived from any softtissue of the body. Such soft tissue connects, supports, or surroundsvarious structures and organs of the body, including, but not limitedto, smooth muscle, skeletal muscle, tendons, fibrous tissues, fattytissue, blood and lymph vessels, perivascular tissue, nerves,mesenchymal cells and synovial tissues. Thus, soft tissue cancers can beof fat tissue, muscle tissue, nerve tissue, joint tissue, blood vessels,lymph vessels, and fibrous tissues. Soft tissue cancers can be benign ormalignant. Generally, malignant soft tissue cancers are referred to assarcomas, or soft tissue sarcomas. There are many types of soft tissuetumors, including lipoma, lipoblastoma, hibernoma, liposarcoma,leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, neurofibroma,schwannoma (neurilemoma), neuroma, malignant schwannoma,neurofibrosarcoma, neurogenic sarcoma, nodular tenosynovitis, synovialsarcoma, hemangioma, glomus tumor, hemangiopericytoma,hemangioendothelioma, angiosarcoma, Kaposi sarcoma, lymphangioma,fibroma, elastofibroma, superficial fibromatosis, fibrous histiocytoma,fibrosarcoma, fibromatosis, dermatofibrosarcoma protuberans (DFSP),malignant fibrous histiocytoma (MFH), myxoma, granular cell tumor,malignant mesenchymomas, alveolar soft-part sarcoma, epithelioidsarcoma, clear cell sarcoma, and desmoplastic small cell tumor. In aparticular embodiment, the soft tissue cancer is a sarcoma selected fromthe group consisting of a fibrosarcoma, a gastrointestinal sarcoma, aleiomyosarcoma, a dedifferentiated liposarcoma, a pleomorphicliposarcoma, a malignant fibrous histiocytoma, a round cell sarcoma, anda synovial sarcoma.

Another aspect of the present teachings relates to a method of treatinga subject with autoimmune diseases comprising administering to thesubject an effective amount of a compound described herein. In oneembodiment, the compounds described herein inhibit the growth of atumor.

The autoimmune diseases include, but not limited to, rheumatoidarthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis(MS), Crohn's disease, psoriasis and asthma.

Another aspect of the present teachings relates to a method of treatinga subject with auto-inflammatory diseases comprising administering tothe subject an effective amount of a compound described herein.

The auto-inflammatory diseases include, but not limited to, familialMediterranean fever (FMF), Tumor Necrosis Factor (TNF)receptor-associated periodic syndrome (TRAPS), mevalonate kinasedeficiency/hyperimmunoglobulin D syndrome (MKD/HIDS), Muckle-Wellssyndrome (MWS), familial cold autoinflammatory syndrome (FCAS),neonatal-onset multisystem inflammatory disease (NOMID), periodic fever,aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome), pyogenicsterile arthritis, pyoderma gangrenosum, acne (PAPA), deficiency of theinterleukin-1 receptor antagonist (DIRA), Behcet's disease, MajeedSyndrome, Chronic recurrent multifocal osteomyelitis (CRMO), Schnitzlersyndrome, and Blau syndrome.

In some embodiments, the present teachings provide methods of treating asubject with a cancer comprising administering to the subject aneffective amount of a compound represented by Structural Formula (I) incombination with an effective anti-cancer therapy. In one embodiment,the cancer is a metastatic cancer. A “metastatic cancer” is a cancerthat has spread from its primary site to other parts of the body.

The anti-cancer therapy described herein includes administration of ananti-cancer agent. An “anti-cancer agent” is a compound, which whenadministered in an effective amount to a subject with cancer, canachieve, partially or substantially, one or more of the following:arresting the growth, reducing the extent of a cancer (e.g., reducingsize of a tumor), inhibiting the growth rate of a cancer, andameliorating or improving a clinical symptom or indicator associatedwith a cancer (such as tissue or serum components) or increasinglongevity of the subject.

The anti-cancer agents suitable for use in the methods described hereininclude any anti-cancer agents that have been approved for the treatmentof cancer. In one embodiment, the anti-cancer agent includes, but is notlimited to, a targeted antibody, an angiogenesis inhibitor, analkylating agent, an antimetabolite, a vinca alkaloid, a taxane, apodophyllotoxin, a topoisomerase inhibitor, a hormonal antineoplasticagent and other antineoplastic agents.

In one embodiment, the anti-cancer agents that can be used in methodsdescribed herein include, but are not limited to, paclitaxel, docetaxel,5-fluorouracil, trastuzumab, lapatinib, bevacizumab, letrozole,goserelin, tamoxifen, cetuximab, panitumumab, gemcitabine, capecitabine,irinotecan, oxaliplatin, carboplatin, cisplatin, doxorubicin,epirubicin, cyclophosphamide, methotrexate, vinblastine, vincristine,melphalan, cytarabine, etoposide, daunorubicin, bleomycin, mitomycin andadriamycin and a combination thereof.

In one embodiment, the anti-cancer agent and the compound represented byStructural Formula (I) are administered contemporaneously. Whenadministered contemporaneously, the anti-cancer agent and the compoundcan be administered in the same formulation or in differentformulations. Alternatively, the compound and the additional anti-canceragent are administered separately at different times.

The term an “effective amount” means an amount when administered to thesubject which results in beneficial or desired results, includingclinical results, e.g., inhibits, suppresses or reduces the cancer(e.g., as determined by clinical symptoms or the amount of cancer cells)in a subject as compared to a control.

As used herein, “treating a subject with a cancer” includes achieving,partially or substantially, one or more of the following: arresting thegrowth, reducing the extent of the cancer (e.g., reducing size of atumor), inhibiting the growth rate of the cancer, ameliorating orimproving a clinical symptom or indicator associated with the cancer(such as tissue or serum components) or increasing longevity of thesubject; and reducing the likelihood of recurrence of the cancer.

Generally, an effective amount of a compound taught herein variesdepending upon various factors, such as the given drug or compound, thepharmaceutical formulation, the route of administration, the type ofdisease or disorder, the identity of the subject or host being treated,and the like, but can nevertheless be routinely determined by oneskilled in the art. An effective amount of a compound of the presentteachings may be readily determined by one of ordinary skill by routinemethods known in the art.

In an embodiment, an effective amount of a compound taught herein rangesfrom about 0.1 to about 1000 mg/kg body weight, alternatively about 1 toabout 500 mg/kg body weight, and in another alternative, from about 20to about 300 mg/kg body weight. In another embodiment, an effectiveamount of a compound taught herein ranges from about 0.5 to about 5000mg/m², alternatively about from 5 to about 2500 mg/m², and in anotheralternative from about 50 to about 1000 mg/m². The skilled artisan willappreciate that certain factors may influence the dosage required toeffectively treat a subject suffering from cancer or reduce thelikelihood of recurrence of a cancer. These factors include, but are notlimited to, the severity of the disease or disorder, previoustreatments, the general health and/or age of the subject and otherdiseases present.

Moreover, for methods described herein (including treating a subjectwith a cancer or reducing the likelihood of recurrence of a cancer), a“treatment” or dosing regimen of a subject with an effective amount ofthe compound of the present teachings may consist of a singleadministration, or alternatively comprise a series of applications. Forexample, the compound of the present teachings may be administered atleast once a week. However, in another embodiment, the compound may beadministered to the subject from about one time per week to once dailyfor a given treatment. The length of the treatment period depends on avariety of factors, such as the severity of the disease, the age of thepatient, the concentration and the activity of the compounds of thepresent teachings, or a combination thereof. It will also be appreciatedthat the effective dosage of the compound used for the treatment mayincrease or decrease over the course of a particular treatment regime.Changes in dosage may result and become apparent by standard diagnosticassays known in the art. In some instances, chronic administration maybe required.

A “subject” is a mammal, preferably a human, but can also be an animalin need of veterinary treatment, e.g., companion animals (e.g., dogs,cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, andthe like) and laboratory animals (e.g., rats, mice, guinea pigs, and thelike).

The compounds taught herein can be administered to a patient in avariety of forms depending on the selected route of administration, aswill be understood by those skilled in the art. The compounds of thepresent teachings may be administered, for example, by oral, parenteral,buccal, sublingual, nasal, rectal, patch, pump or transdermaladministration and the pharmaceutical compositions formulatedaccordingly. Parenteral administration includes intravenous,intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal,intrapulmonary, intrathecal, rectal and topical modes of administration.Parenteral administration can be by continuous infusion over a selectedperiod of time.

The compounds taught herein can be suitably formulated intopharmaceutical compositions for administration to a subject. Thepharmaceutical compositions of the present teachings optionally includeone or more pharmaceutically acceptable carriers and/or diluentstherefor, such as lactose, starch, cellulose and dextrose. Otherexcipients, such as flavoring agents; sweeteners; and preservatives,such as methyl, ethyl, propyl and butyl parabens, can also be included.More complete listings of suitable excipients can be found in theHandbook of Pharmaceutical Excipients (5^(th) Ed., Pharmaceutical Press(2005)). A person skilled in the art would know how to prepareformulations suitable for various types of administration routes.Conventional procedures and ingredients for the selection andpreparation of suitable formulations are described, for example, inRemington's Pharmaceutical Sciences (2003—20th edition) and in TheUnited States Pharmacopeia: The National Formulary (USP 24 NF19)published in 1999. The carriers, diluents and/or excipients are“acceptable” in the sense of being compatible with the other ingredientsof the pharmaceutical composition and not deleterious to the recipientthereof.

Typically, for oral therapeutic administration, a compound of thepresent teachings may be incorporated with excipient and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like.

Typically for parenteral administration, solutions of a compound of thepresent teachings can generally be prepared in water suitably mixed witha surfactant such as hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, DMSO and mixturesthereof with or without alcohol, and in oils. Under ordinary conditionsof storage and use, these preparations contain a preservative to preventthe growth of microorganisms.

Typically, for injectable use, sterile aqueous solutions or dispersionof, and sterile powders of, a compound described herein for theextemporaneous preparation of sterile injectable solutions ordispersions are appropriate.

For nasal administration, the compounds of the present teachings can beformulated as aerosols, drops, gels and powders. Aerosol formulationstypically comprise a solution or fine suspension of the active substancein a physiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomizing device. Alternatively, the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal after use. Where the dosage form comprises an aerosoldispenser, it will contain a propellant which can be a compressed gassuch as compressed air or an organic propellant such asfluorochlorohydrocarbon. The aerosol dosage forms can also take the formof a pump-atomizer.

For buccal or sublingual administration, the compounds of the presentteachings can be formulated with a carrier such as sugar, acacia,tragacanth, or gelatin and glycerine, as tablets, lozenges or pastilles.

For rectal administration, the compounds described herein can beformulated in the form of suppositories containing a conventionalsuppository base such as cocoa butter.

The compounds of invention may be prepared by methods known to thoseskilled in the art, as illustrated by the general schemes and proceduresbelow and by the preparative examples that follow. All startingmaterials are either commercially available or prepared by methods knownto those skilled in the art and the procedures described below.

General synthetic approaches to the 1H-indazole core have been reviewedin literature (Schmidt A. et al. Eur. J. Org. Chem. 2008, 4073-4095).

In one approach, the 5H-pyrrolo[3,2-d]pyrimidine ring can be activatedthrough a deportation followed by electrophilic quenching effectivelyintroducing halogens (e.g. Br, I) or metals (e.g. SnR₃, B(OR)₂)(Scheme 1) appropriate to undergo cross-coupling reactions asexemplified by Suzuki-Miyarua cross coupling that also cleaves the arylarylsulfonamide group. The final amination can be facilitated by asuitable metal catalyst with or without an introduction of theadditional protecting group. The same transformation can be achievedunder a S_(N)Ar reaction at high temperatures.

In another approach, the ring can be synthesized in a sequence initiatedby a Sonogashira reaction followed by a base induced ring closure ofintermediate 9 (Scheme 2). Commercially available pyrimidine 8 can bealso be synthesized in a number of approaches presented in Scheme byintroduction of the missing functionalities through amination of 6 orhalogenation of 7.

EXEMPLIFICATION Example A: Synthesis

General Methods

Commercially available starting materials, reagents, and solvents wereused as received. In general, anhydrous reactions were performed underan inert atmosphere such as nitrogen or Argon. PoraPak® Rxn CX refers toa commercial cation-exchange resin available from Waters.

Microwave reactions were performed with a Biotage Initiator microwavereactor. Reaction progress was generally monitored by TLC using Mercksilica gel plates with visualization by UV at 254 nm, by analytical HPLCor by LCMS (Bruker Exquire 4000). Flash column chromatographicpurification of intermediates or final products was performed using230-400 mesh silica gel 60 from EMD chemicals or Silicycle, or purifiedusing a Biotage Isolera with KP-SIL or HP-SIL silica cartridges, orKP-NH basic modified silica and corresponding samplets. Reverse-phaseHPLC purification was performed on a Varian PrepStar model SD-1 HPLCsystem with a Varian Monochrom 10u C-18 reverse-phase column using a ofabout 5-30% MeCN or MeOH/0.05 TFA-H₂O to 70-90% MeCN or MeOH/0.05%TFA-H₂O over a 20-40-min period at a flow rate of 30-50 mL/min. Reversephase purification was also performed using a Biotage Isolera equippedwith a KP-C₁₈-HS column using a gradient between 5-95% MeOH (orMeCN)/0.1% TFA in H₂O. Proton NMRs were recorded on a Bruker 400 MHzspectrometer, and mass spectra were obtained using a Bruker Esquire 4000spectrometer.

Compound names were generated using the software built intoCambridgeSoft-PerkinElmer's ChemBioDraw Ultra version 11.0 or 12.0.

Abbreviations

-   Ac Acetyl-   aq aqueous-   anh anhydrous-   Ar argon (in the experimental part); aromatic/heteroaromatic group    in schemes-   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   Boc tert-butoxycarbonyl-   br. broad-   calcd calculated-   d doublet (only when used within 1H NMR spectra)-   d day-   DCM dichloromethane-   DIPEA diisopropylethylamine-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   dppf 1,1′-bis(diphenylphosphino)ferrocene-   h hour-   hal halogen-   HPLC high performance liquid chromatography-   I.P. Intraperitoneal injection-   LC-MS liquid chromatography coupled to mass spectrometry-   LDA lithium diisopropylamide-   min minute-   m multiplet-   mw microwave irradiation-   MS ESI mass spectra, electrospray ionization-   ND not determined-   NMP 1-methyl-2-pyrrolidone-   NMR nuclear magnetic resonance-   O/N overnight-   pin pinacol-   prep preparative-   p.o. oral administration-   Q.D. dosed once a day-   Q.W. dosed once weekly-   rt room temperature-   RP reverse phase-   s singlet-   satd saturated-   SMs starting materials-   S_(N)Ar Nucleophilic Aromatic Substitution-   SPE solid phase extraction-   t triplet-   TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   temp. temperature-   TFA trifluoroacetic acid-   TLC thin layer chromatography-   THF tetrahydrofuran-   xs excess-   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene    Preparation of Starting Materials    General Method A (Sonogashira Coupling, Preparation of    2-chloro-4-(Ar/alkylethynyl)pyrimidin-5-amine)

Halopyrimidine (1.0 equiv), acetylene (1 equiv) in Et₃N (0.9 M) or inEt₃N/DMF (1:1 v/v, 0.8 M) were degassed with Ar, charged with CuI(0.1-0.2 euiv) and Pd(PPh₃)₂Cl₂ (0.03 equiv) or Pd(PPh₃)₄ (0.07 equiv)and heated sealed at 100° C. until completion. The reaction was cooledto rt, filtered or alternatively concentrated under reduced pressure andsubjected to aqueous workup before purification by trituration or flashchromatography.

General Method B (t-BuOK—Induced Cyclization)

A solution of 2-chloro-4-(aryl(alkyl)ethynyl)pyrimidin-5-amine in anhNMP (0.25 M) was treated with t-BuOK (2 equiv) added in one portion atrt (exothermic). The reaction was stirred briefly at rt and then at 50°C. for 0.5-1 h. Later, the reaction was cooled to rt and diluted withH₂O. The product was collected by filtration and rinsing with H₂O.

General Method C (Buchwald-Hartwig Pd-Catalyzed Amination)

A dry vial was charged with 2-chloro-5H-pyrrolo[3,2-d]pyrimidine ortert-butyl 2-chloro-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (1 equiv),K₂CO₃ (10 equiv), ArNH₂ (1.8 equiv) and Pd(OAc)₂ (0.1 equiv)_(—) in ahndioxane (0.07 M). The reaction mixture was degassed with Ar and chargedwith Xantphos (0.2 mmol). The reaction vial was sealed, degassing wasrepeated and the reaction was stirred briefly at rt then in an oil bathat 100° C. overnight. Typically the reaction mixture was cooled to rt,filtered using DCM and MeOH to transfer and rinse. The filtrate wasconcentrated under reduced pressure, purified by flash chromatography(EtOAc in DCM or MeOH in DCM). In the case of Boc protected material(some loss of Boc was observed in the first step), the material wastaken into DCM/TFA (5:1 v/v) and stirred at rt for 1 h. The reaction wasthen concentrated under reduced pressure and purified by flashchromatography or/and RP HPLC.

General Method D (Acid Catalyzed Amination)

To a solution of 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine ini-PrOH was added amine or aniline (4-6 equiv) and HCl in dioxane (4 M, 2equiv). Alternatively an HCl salt of an amine (4-6 equiv) and DIPEA (2-4equiv) were used. Sealed vial was subjected to microwave irradiation at170° C. for 2-8 h in a microwave reactor (high pressure: >10 bar). Thereaction mixture was purified by reverse phase chromatography.

General Method E (Suzuki-Miyaura Coupling)

To a degassed mixture of dioxane (49 mL) and H₂O (12 mL),2-chloro-6-iodo-5-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidine (0.744 g,1.8 mmol), o-tolylboronic acid (0.264 g, 1.9 mmol), K₂CO₃ (1.01 g, 7.3mmol) was added Pd(dppf)Cl₂.DCM (0.145 g, 0.18 mmol). Degassing wasrepeated and the reaction was heated in an oil bath under Ar at 105° C.overnight. The reaction then was cooled, concentrated under reducedpressure and purified by flash chromatography (EtOAc-DCM—10%)

General Method F (Protection with Boc Group)

5H-pyrrolo[3,2-d]pyrimidine, Boc₂O (2-4 equiv), DMAP (0.2-0.4 equiv) andDIPEA (1.5 equiv) were stirred in EtOAc at rt overnight. The reactionwas then concentrated under reduced pressure and purified by flashchromatography.

INTERMEDIATES Synthesis of 2-(4-(3-aminophenyl)piperazin-1-yl)ethanol

A. 2-hydroxy-1-(4-(3-nitrophenyl)piperazin-1-yl)ethanone

An anh DMF (10 mL) solution of 1-(3-nitrophenyl)piperazine (0.67 g, 3.2mmol), 2-hydroxyacetic acid (0.261 g, 3.4 mmol), DIPEA (1.2 mL, 6.9mmol) was treated with TBTU (1.10 g, 3.4 mmol) added in one portion atrt. The reaction was stirred at rt for 2 h, diluted with xs H₂O and iceand filtered to afford2-hydroxy-1-(4-(3-nitrophenyl)piperazin-1-yl)ethanone as a yellow solid(0.546 g, 64%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.66 (t, J=2.10 Hz, 1H),7.60 (d, J=7.78 Hz, 1H), 7.48 (t, J=8.20 Hz, 1H), 7.40 (dd, J=8.30, 2.10Hz, 1H), 4.69 (t, J=5.50 Hz, 1H), 4.13 (d, J=5.50 Hz, 2H), 3.56-3.66 (m,4H), 3.23-3.32 (m, 4H); MS ESI [M+H]⁺266.2 cald for[C₁₂H₁₅N₃O₄+H]⁺266.11.

B. 1-(4-(3-aminophenyl)piperazin-1-yl)-2-hydroxyethanone

2-Hydroxy-1-(4-(3-nitrophenyl)piperazin-1-yl)ethanone (0.546 g, 2.06mmol) and Pd/C (224 mg, 0.2 mmol) were stirred in MeOH (200 mL) under H₂(1 atm) at rt 1 d. The reaction was filtered through Celite, rinsing thereaction flask and the filtration pad with MeOH. Concentration underreduced pressure provided1-(4-(3-aminophenyl)piperazin-1-yl)-2-hydroxyethanone as a white solid(0.404 g, 83%)). ¹H NMR (400 MHz, CD₃OD) δ ppm 7.00 (t, J=8.00 Hz, 1H),6.39 (s, 1H), 6.37 (d, J=8.00 Hz, 1H), 6.30 (d, J=8.00 Hz, 1H), 4.27 (s,2H), 3.68-3.79 (m, 2H), 3.49-3.58 (m, 2H), 3.12 (d, J=4.77 Hz, 4H); MSESI [M+H]⁺236.2 cald for [C₁₂H₁₇N₃O₂+H]⁺235.28.

C. 2-(4-(3-Aminophenyl)piperazin-1-yl)ethanol

An anh THF (24 mL) solution of1-(4-(3-aminophenyl)piperazin-1-yl)-2-hydroxyethanone (0.404 g, 1.72mmol) under Ar was treated with LiAlH₄ (1.0 M in THF, 6.9 mL, 6.9 mmol)added dropwise at 0° C. After additional 5 min, the cooling bath wasremoved and the reaction was allowed to warm to rt and then heated atreflux overnight. The reaction mixture was then cooled to rt and pouredcarefully (dropwise) to a stirred suspension of xs Na₂SO₄.10H₂O in DCMat 0° C. Later the reaction was stirred for 30 min at rt and filtered toafford 2-(4-(3-aminophenyl)piperazin-1-yl)ethanol as a light tan gumthat was used without further purification (0.52 g). ¹H NMR (400 MHz,CD₃OD) δ ppm 6.99 (t, J=8.03 Hz, 1H), 6.40 (s, 1H), 6.37 (d, J=8.03 Hz,1H), 6.29 (d, J=8.03 Hz, 1H), 3.73 (t, J=6.00 Hz, 2H), 3.12-3.19 (m,4H), 3.04-3.11 (m, 2H), 2.93-2.98 (m, 2H), 2.59 (t, J=6.00 Hz, 2H); MSESI [M+H]⁺222.2 cald for [C₁₂H₁₉N₃O+H]⁺222.15.

Synthesis of 2-chloro-4-(phenylethynyl)pyrimidin-5-amine

A. -Chloro-N-(diphenylmethylene)-4-(phenylethynyl)pyrimidin-5-amine

5-Bromo-2-chloro-4-(phenylethynyl)pyrimidine (WO2013/078254 p. 166)(0.82 g, 2.9 mmol), diphenylmethanimine (0.58 g, 3.2 mmol), Pd(OAc)₂ (26mg, 0.11 mmol) and Cs₂CO₃ (1.40 g, 4.3 mmol) in anh PhMe (32 mL) weredegassed with Ar before BINAP (108 mg, 0.17 mmol) was added. Thereaction was heated sealed in an oil bath at 105° C. for 17 h, cooled tort, diluted with DCM and filtered through a 2 um frit. Concentrationunder reduced pressure and purification by flash chromatography(DCM-EtOAc) afforded2-chloro-N-(diphenylmethylene)-4-(phenylethynyl)pyrimidin-5-amine as anorange gum (0.71 g). MS ESI [M+H]⁺394.2 cald for [C₂₅H₁₆ClN₃+H]⁺394.1.

B. 2-Chloro-4-(phenylethynyl)pyrimidin-5-amine

2-Chloro-N-(diphenylmethylene)-4-(phenylethynyl)pyrimidin-5-amine (0.28g, 0.71 mmol) was stirred in THF (6 mL) and aq HCl (2.7 M, 1.5 mL) for23 h at rt. The reaction was taken into EtOAc, washed with satd aqNaHCO₃, dried (Na₂SO₄), concentrated under reduced pressure and purifiedby flash chromatography (DCM-MeOH) to afford2-chloro-4-(phenylethynyl)pyrimidin-5-amine (116 mg, 72%) as a lightyellow solid. MS ESI [M+H]⁺230.1, cald for [C₁₂H₈ClN₃+H]⁺230.04.

Synthesis of 2-chloro-4-(o-tolylethynyl)pyrimidin-5-amine

A solution of 2,4-dichloropyrimidin-5-amine (4.92 g, 30 mmol),1-ethynyl-2-methylbenzene (3.63 g, 33 mmol), CuI (0.57 g, 3.0 mmol),Pd(PPh₃)₄, (3.43 g, 2.1 mmol) in Et₃N (20 mL) and DMF (20 mL) washeating in an oil bath at 100° C. for 3 h. H₂O and EtOAc were added, thephases were separated and the aqueous layer was extracted with moreEtOAc. The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude product was trituratedwith Et₂O to give the title compound as a yellow solid (5.92 g, 81%).

TABLE 1 Intermediates synthesized according to General Method A. Yield;MS calcd; Appearance; IUPAC name Structure MS ESI [M + H]⁺; Salt form2-chloro-4-((2- chlorophenyl)ethynyl) pyrimidin-5-amine

[C₁₂H₇Cl₂N₃ + H]⁺ 264.0; 264.1 0.64 g (66%) light tan solid; free baseSMs: 2,4-dichloropyrimidin-5-amine (0.602 g, 3.7 mmol),1-chloro-2-ethynylbenzene (0.506 g, 3.7 mmol), CuI (0.126 g, 0.66 mmol),Pd(PPh₃)₂Cl₂ (0.130 g, 0.18 mmol), DMF (10 mL), Et₃N (10 mL), mw/100°C./2 h ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (s, 1 H), 7.91 (d, J = 7.80Hz, 1 H), 7.63 (d, J = 7.50 Hz, 1 H), 7.52 (t, J = 7.50 Hz, 1 H), 7.45(t, J = 7.30 Hz, 1 H), 6.14 (brs, 2 H) 2-chloro-4-((2,6-dimethylphenyl)ethynyl) pyrimidin-5-amine

C₁₄H₁₂ClN₃ + H]⁺ 258.08; 258.2 0.173 g (83%); yellow solid; free baseSMs: 2,4-dichloropyrimidin-5-amine (0.17 g, 0.81 mmol),2-ethynyl-1,3-dimethylbenzene (0.12 g, 0.89 mmol), CuI (0.015 g, 0.081mmol), Pd(PPh₃)₄ (0.14 g, 0.12 mmol) ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.22-8.29 (m, 1 H), 7.24-7.31 (m, 1 H), 7.14-7.22 (m, 2 H), 5.93 (br. S,2 H), 2.44-2.48 (m, 6 H) 2-chloro-4- (cyclopentylethynyl)pyrimidin-5-amine

[C₁₁H₁₂ClN₃ + H]⁺ 222.08; 222.1 124 mg (28%); yellow solid; free baseSMs: 2,4-dichloropyrimidin-5-amine (328 mg, 2.0 mmol),ethynylcyclopentane (207 mg, 2.2 mmol), CuI (38 mg, 0.20 mmol),Pd(PPh₃)₄ (347 mg, 0.30 mmol) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.13 (s, 1H), 5.81 (s, 2 H), 2.88-3.02 (m, 1 H), 1.89- 2.05 (m, 2 H), 1.62-1.76(m, 4 H), 1.49-1.61 (m, 2 H) 2-chloro-4-(o- tolylethynyl)pyrimidin-5-amine

[C₁₃H₁₀ClN₃ + H]⁺ 244.07; 244.1 5.92 g (81%); yellow solid; free baseSMs: 2,4-dichloropyrimidin-5-amine (4.92 g mmol, 30 mmol),1-ethynyl-2-methylbenzene (3.63 g, 33 mmol). ¹H NMR (400 MHz, DMSO-d₆) δppm 8.24 (s, 1 H), 7.74 (d, J = 7.53 Hz, 1 H), 7.33-7.43 (m, 2 H),7.24-7.32 (m, 1 H), 6.10 (s, 2 H), 2.48 (s, 3 H) 2-chloro-4-(thiophen-3-ylethynyl)pyrimidin-5- amine

[C₁₀H₆ClN₃S + H]⁺ 236.01; 236.1 146 mg (31%) yellow solid; free baseSMs: 2,4-dichloropyrimidin-5-amine (328 mg, 2 mmol), 3-ethynylthiophene(238 mg, 2.2 mmol), CuI (38 mg, 0.20 mmol), Pd(PPh₃)₄ (347 mg, 0.30mmol) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.20 (s, 1 H), 8.11-8.15 (m, 1 H),7.64-7.70 (m, 1 H), 7.41 (d, J = 5.02 Hz, 1 H), 6.08-6.18 (m, 2 H)2-chloro-4-((2- fluorophenyl)ethynyl) pyrimidin-5-amine

[C₁₂H₇ClFN₃ + H]⁺ 248.04; 2 48.1 562 mg (76%); yellow solid; free baseSMs: 2,4-dichloropyrimidin-5-amine (492 mg, .03 mmol),ethynyl-2-fluorobenzene (396 mg, 3.3 mmol), CuI (57 mg, 0.30 mmol),Pd(PPh₃)₄ (520 mg, 0.45 mmol) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.25 (s, 1H), 7.84-7.91 (m, 1 H), 7.53-7.61 (m, 1 H), 7.29-7.43 (m, 2 H), 6.21 (s,2 H) 2-chloro-4-((tetrahydro- 2H-pyran-4- yl)ethynyl)pyrimidin-5- amine

[C₁₁H₁₂ClN₃O + H]⁺ 238.08; 238.1 610 mg (86%); yellow solid free baseSMs: 2,4-dichloropyrimidin-5-amine (492 mg, 3 mmol),4-ethynyltetrahydro-2H-pyran-(363 mg, 3.3 mmol), CuI (57 mg, 0.30 mmol),Pd(PPh₃)₄ (520 mg, 0.45 mmol) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.14 (s, 1H), 3.88-3.98 (m, 2 H), 3.51-3.61 (m, 2 H), 3.00-3.09 (m, 1 H),1.91-2.02 (m, 2 H), 1.75-1.85 (m, 2 H) 2-chloro-4-((2-methoxyphenyl)ethynyl) pyrimidin-5-amine

[C₁₃H₁₀ClN₃O + H]⁺ 260.06; 260.2 1.81 g (70%); yellow solid; free baseSMs: 2,4-dichloropyrimidin-5-amine 1.64 g, 10 mmol),ethynyl-2-methoxybenzene (1.45 g, 11 mmol), CuI (198 mg, 1.0 mmol),Pd(PPh₃)₄ (1.16 g, 1.0 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 8.16 (s, 1H), 7.55 (d, J = 7.78 Hz, 1 H), 7.43 (t, J = 7.91 Hz, 1 H), 6.91-7.05(m, 2 H), 4.61 (br. s., 2 H), 3.95 (s, 3 H)

Synthesis of 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine by GeneralMethod A

t-BuOK (5.65 g, 50.4 mmol) was added to an NMP (100 mL) solution of2-chloro-4-(o-tolylethynyl)pyrimidin-5-amine (5.92 g, 24 mmol) at 0° C.The reaction was warmed to rt and stirred for 1 h. The reaction mixturewas then cooled to 0° C. and 2 M aq HCl was added to neutralize (pH7.0). H₂O and EtOAc were added, the phases were separated and theaqueous layer was extracted with EtOAc. The combined organic extractswere dried (Na₂SO₄), filtered and concentrated under reduced pressure.The crude product was triturated with Et₂O and filtered. The filtratewas concentrated under reduced pressure and purified by flashchromatography (100 g SiO₂, 0-40% EtOAc/hexanes) to give a yellow solidthat was combined with the product isolated by the filtration (4.46 g,75%).

Synthesis of 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine viaSuzuki-Miyaura Coupling

A. 2-Chloro-5-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidine

t-BuOK (0.780 g, 6.9 mmol) was added in four portions to2-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.861 g, 5.6 mmol) in anh THF (40mL) with cooling in a H₂O bath. The reaction was stirred for 10 min,PhSO₂Cl was added over 15 min (0.9 mL, 7.0 mmol) and the reaction wasleft stirring overnight at rt. THF was removed under reduced pressure,the residue was taken into EtOAc, washed with brine (2×) and dried(Na₂SO₄) to afford2-chloro-5-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidine as a white solid(1.59 g, 97%) that was used without further purification. ¹H NMR (400MHz, CDCl₃) δ ppm 9.22 (s, 1H), 7.91-7.99 (m, 3H), 7.65-7.71 (m, 1H),7.52-7.60 (m, 2H), 6.82 (d, J=3.76 Hz, 1H); MS ESI [M+H]⁺ 294.1, caldfor [C₁₂H₈ClN₃O₂S+H]⁺294.0.

A. 2-Chloro-6-iodo-5-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidine

LDA (6.2 mL, 1.0 M in THF, 6.2 mmol) was added dropwise over 8 min toanh THF (95 mL) solution of2-chloro-5-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidine (1.59 g, 5.4mmol) stirred at −78° C. under Ar. The reaction was then stirred at thetemperature for 80 min before I₂ (1.58 g, 6.2 mmol in anh THF 4 mL) wasadded over several minutes via cannula. The stirring with cooling wascontinued for 3 h, then the cooling bath was removed and after 45 minH₂O (20 mL) was added. The reaction was diluted with DCM (500 mL),washed (brine, 2×), dried (Na₂SO₄) and concentrated under reducedpressure. Purification by flash chromatography (EtOAc-DCM 0-10%)afforded 2-chloro-6-iodo-5-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidineas a white solid (1.05 g, 46%). MS ESI [M+H]⁺ 419.9, cald for[C₁₂H₇ClIN₃O₂S+H]⁺419.9.

B. 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine

To a degassed mixture of dioxane (49 mL) and H₂O (12 mL),2-chloro-6-iodo-5-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidine (0.744 g,1.8 mmol), o-tolylboronic acid (0.264 g, 1.9 mmol), K₂CO₃ (1.01 g, 7.3mmol) was added Pd(dppf)Cl₂.DCM (0.145 g, 0.18 mmol). Degassing wasrepeated and the reaction was heated in an oil bath under Ar at 105° C.overnight. The reaction then was cooled, concentrated under reducedpressure and purified by flash chromatography (EtOAc-DCM 0-10%) toafford 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine as a white solid(0.32 g, 74%). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.72 (s, 1H), 7.55 (d,J=7.28 Hz, 1H), 7.32-7.43 (m, 3H), 6.69 (s, 1H), 2.49 (s, 3H); MS ESI[M+H]⁺244.1, cald for [C₁₃H₁₀ClN₃+H]⁺244.06.

Table 2 The following intermediates were synthesized according toGeneral Method B:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺; Saltform 2-chloro-6-(2-chlorophenyl)- 5H-pyrrolo[3,2-d]pyrimidine

[C₁₂H₇Cl₂N₃ + H]⁺ 264.0; 264.1 0.193 g (97%); light tan solid; free baseSMs: 2-chloro-4-((2-chlorophenyl)ethynyl)pyrimidin-5-amine (198 mg, 0.75mmol), NMP (3 mL), t-BuOK (188 mg, 1.7 mmol) ¹H NMR (400 MHz, CD₃OD) δppm 8.78 (s, 1 H), 7.71-7.77 (m, 1 H), 7.61-7.67 (m, 1 H), 7.48-7.54 (m,2 H), 6.93 (s, 1 H) 2-chloro-6-(o-tolyl)-5H- pyrrolo[3,2-d]pyrimidine

[C₁₃H₁₀ClN₃ + H]⁺ 244.06; 244.2 4.46 g (75%); a yellow solid; free baseSMs: 2-chloro-4-(o-tolylethynyl)pyrimidin-5-amine (5.92 g, 24 mmol) ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.32 (br. s., 1 H), 8.78 (s, 1 H), 7.57(d, J = 7.03 Hz, 1 H), 7.31-7.46 (m, 3 H), 6.73-6.81 (m, 1 H), 2.45 (s,3 H) 2-chloro-6-(2,6- dimethylphenyl)-5H- pyrrolo[3,2-d]pyrimidine

[C₁₄H₁₂ClN₃ + H]⁺ 258.09; 258.2 94 mg (56%) yellow solid; free base SMs:2-chloro-4-((2,6-dimethylphenyl)ethynyl)pyrimidin-5-amine (168 mg, 0.65mmol), t- BuOK (219 mg, 2.0 mmol) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.26(br. s., 1 H), 8.76 (s, 1 H), 7.26-7.35 (m, 1 H), 7.15-7.23 (m, 2 H),6.56 (s, 1 H), 2.08 (s, 6 H) 2-chloro-6-cyclopentyl-5H-pyrrolo[3,2-d]pyrimidine

[C₁₁H₁₂ClN₃ + H]⁺ 222.08 222.2 82 mg (66%) yellow solid; free base SMs:2-chloro-4-(cyclopentylethynyl)pyrimidin-5-amine (124 mg, 0.56 mmol),t-BuOK (157 mg, 1.4 mmol) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.96 (br. s.,1 H), 8.63 (s, 1 H), 6.38 (s, 1 H), 2.02- 2.22 (m, 3 H), 1.84-1.95 (m, 1H), 1.62-1.81 (m, 5 H) 2-chloro-6-(thiophen-3-yl)-5H-pyrrolo[3,2-d]pyrimidine

[C₁₀H₆ClN₃S + H]⁺ 236.01; 236.1 128 mg (88%); yellow solid; free baseSms: 2-chloro-4-(thiophen-3-ylethynyl)pyrimidin-5-amine (146 mg, 0.62mmol), t-BuOK (174 mg, 1.6 mmol) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.50(br. s., 1 H), 8.74 (s, 1 H), 8.25 (s, 1 H), 7.76 (s, 2 H), 6.97-7.02(m, 1 H) 2-chloro-6-(2-fluorophenyl)- 5H-pyrrolo[3,2-d]pyrimidine

[C₁₂H₇ClFN₃ + H]⁺ 248.04; 248.1 414 mg (74%); yellow solid; free baseSMs: 2-chloro-4-((2-fluorophenyl)ethynyl)pyrimidin-5-amine (562 mg, 2.3mmol), t-BuOK (637 mg, 5.7 mmol) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.76 (s,1 H), 7.90-7.98 (m, 1 H), 7.61-7.69 (m, 2 H), 7.50-7.60 (m, 1 H),7.30-7.42 (m, 1 H), 7.02 (s, 1 H) 2-chloro-6-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[3,2- d]pyrimidine

[C₁₁H₁₂ClN₃O + H]⁺ 238.08; 238.1 439 mg (72%); yellow solid; free baseSms: 2-chloro-4-((tetrahydro-2H-pyran-4-yl)ethynyl)pyrimidin-5-amine(610 mg, 2.6 mmol), t-BuOK (720 mg, 6.4 mmol) ¹H NMR (400 MHz, CD₃OD) δppm 8.59 (s, 1 H), 6.41 (s, 1 H), 4.02-4.10 (m, 2 H), 3.60 (s, 2 H),3.11-3.23 (m, 1 H), 1.94-2.03 (m, 2 H), 1.80-1.94 (m, 2 H)2-chloro-6-(2- methoxyphenyl)-5H- pyrrolo[3,2-d]pyrimidine

[C₁₃H₁₀ClN₃O + H]⁺ 260.06; 260.2 1.59 g (88%); yellow solid; free baseSMs: 2-chloro-4-((2-methoxyphenyl)ethynyl)pyrimidin-5-amine (1.81 g, 7.0mmol), ), t- BuOK (1.96 g, 18 mmol) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.70(s, 1 H), 7.89 (d, J = 6.78 Hz, 1 H), 7.43-7.52 (m, 1 H), 7.22 (d, J =8.28 Hz, 1 H), 7.12 (t, J = 7.53 Hz, 1 H), 6.99 (s, 1 H), 4.04 (s, 3 H)

Preparation of Exemplary Compounds of the Invention Synthesis ofN,6-diphenyl-5H-pyrrolo[3,2-d]pyrimidin-2-amine) (Example A1)

A. tert-Butyl2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate

2-Chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (83.8 mg, 0.365 mmol),Boc₂O (350 mg, 1.60 mmol), DMAP (29 mg, 0.23 mmol) and DIPEA (0.1 mL,0.57 mmol) were stirred in EtOAc (24 mL) at rt for 22 h. The reactionwas then concentrated under reduced pressure and purified by flashchromatography (0 to 30% EtOAc in DCM) to afford tert-butyl2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate as a whitesolid (0.106 g, 88%). ¹H NMR (400 MHz, CDCl₃) δ ppm 9.31 (s, 1H),7.41-7.53 (m, 5H), 6.68 (d, J=0.75 Hz, 1H), 1.37 (s, 9H); MS ESI [M+H]⁺330.2, cald for [C₁₇H₁₆ClN₃O₂+H]⁺330.09.

B. N,6-diphenyl-5H-pyrrolo[3,2-d]pyrimidin-2-amine)

A dry vial was charged with tert-butyl2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (62 mg, 0.19mol), K₂CO₃ (245 mg, 1.8 mmol), PhNH₂ (32 mg, 0.34 mmol) and Pd(OAc)₂(5.6 mg, 0.025 mmol) in ahn dioxane (3 mL). The reaction mixture wasdegassed with Ar and charged with Xantphos (28.5 mg, 0.049 mmol). Thereaction vial was sealed, degassing was repeated and the reaction wasstirred briefly at rt then in an oil bath at 100° C. for 22 h. Thereaction mixture was cooled to rt, filtered using DCM and MeOH totransfer and rinse. The filtrate was concentrated under reduced pressureand purified by flash chromatography (EtOAc in DCM) to afford crudetert-butyl 2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate(MS ESI [M+H]⁺ 387.3, cald for [C₂₃H₂₂N₄O₂+H]⁺387.17) which was takeninto DCM/TFA (25 mL, 5:1 v/v) and stirred at rt for 1 h. The reactionwas then concentrated under reduced pressure and purified by flashchromatography (EtOAc in DCM 0→60%). Trituration with hexanes then withEt₂O-hexanes (1:1 v/v) affordedN,6-diphenyl-5H-pyrrolo[3,2-d]pyrimidin-2-amine as a pale yellow solid(50 mg, 92%). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.70 (s, 1H), 7.95 (d,J=8.30 Hz, 2H), 7.55-7.65 (m, 5H), 7.42-7.49 (m, 2H), 7.26 (t, J=7.50Hz, 1H), 6.91 (s, 1H); MS ESI [M+H]⁺ 287.2, cald for [C₁₈H₁₄N₄+H]′287.12.

Synthesis ofN-(3-morpholinophenyl)-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine(Example A3)

A sealed vial containing2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine (0.73 g, 3.0

mmol), 3-morpholinoaniline (0.71 g, 4.0 mmol), HCl (4 M in dioxane, 1.5mL, 6 mmol) in i-PrOH (10 mL) was heated at 170° C. for 2 h in amicrowave reactor (high pressure). The reaction mixture was purified byreverse phase chromatography and converted to free base using a PoraPakcolumn. The crude product was dissolved in DCM and precipitated usingEt₂O to obtain the title compound as a beige solid (593 mg, 51%). Thetitle compound was suspended in DCM (40 mL) and HCl (1 M in Et₂O, 5 mL)was added. The solution was sonicated until fully dissolved. The mixturewas concentrated in vacuo and triturated with Et₂O to give the titlecompound as a diHCl salt (687 mg, 50%, brown solid).

Table 3 The following examples were prepared according to GeneralMethods C or D

Example number MS calcd; MS ESI [M + H]⁺; Yield; HPLC purity at 254Appearance; IUPAC name Structure nm Salt form N,6-diphenyl-5H-pyrrolo[3,2- d]pyrimidin-2-amine

A1 [C₁₈H₁₄N₄ + H]⁺ 287.12; 287.2; 99.0% 0.050 g (92%); a pale yellowsolid; free base SMs: tert-butyl2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (62 mg, 0.19mol), K₂CO₃ (245 mg, 1.8 mmol), PhNH₂ (32 mg, 0.34 mmol), Pd(OAc)₂ (5.6mg, 0.025 mmol), dioxane (3 mL), Xantphos (28.5 mg, 0.049 mmol). ¹H NMR(400 MHz, CD₃OD) δ ppm 8.70 (s, 1 H), 7.95 (d, J = 8.30 Hz, 2 H),7.55-7.65 (m, 5 H), 7.42-7.49 (m, 2 H), 7.26 (t, J = 7.50 Hz, 1 H), 6.91(s, 1 H) N-(4-((1- methylpiperidin-4- yl)oxy)phenyl)-6- (o-tolyl)-5H-pyrrolo[3,2-d] pyrimidin-2-amine

A2; [C₂₅H₂₇N₅O + H]⁺ 414.22; 414.3; 95.0% 0.0357 g (53 %); pale lightsollid; free base SMs: tert-butyl2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (55.3 mg,0.16 mol), K₂CO₃ (221 mg, 1.6 mmol),4-((1-methylpiperidin-4-yl)oxy)aniline (56.4 mg, 0.27 mmol), Pd(OAc)₂(4.3 mg, 0.019 mmol), dioxane (5 mL), Xantphos (18.5 mg, 0.032 mmol). ¹HNMR (400 MHz, CD₃OD) δ ppm 8.51 (d, J = 1.00 Hz, 1 H), 7.50-7.54 (m, 3H), 7.29- 7.38 (m, 3 H), 6.91-6.95 (m, 2 H), 6.43 (d, J = 0.80 Hz, 1 H),4.30-4.42 (m, 1 H), 2.69- 2.81 (m, 2 H), 2.49 (s, 3 H), 2.35-2.47 (m, 2H), 2.33 (s, 3 H), 1.94-2.08 (m, 2 H), 1.75- 1.92 (m, 2 H) N-(3-morpholnophenyl)- 6-(o-tolyl)-5H- pyrrolo[3,2- d]pyrimidin- 2-amine

A3; [C₂₃H₂₃N₅O + H]⁺ 386.19; 386.2; >99% 0.083 g; (96%); pale yellowsolid; free base SMs: tert-butyl2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (77.3 mg,0.22 mol), K₂CO₃ (311 mg, 2.2 mmol), 3-morpholinoaniline (61 mg, 0.34mml), Pd(OAc)₂ (6.6 mg, 0.029 mmol), dioxane (5 mL), Xantphos (36 mg,0.062 mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.75 (s, 1 H), 7.57 (d, J =7.80 Hz, 1 H), 7.35-7.47 (m, 4 H), 7.20 (s, 1 H), 7.05 (d, J = 8.30 Hz,1 H), 6.96 (dd, J = 8.50, 2.30 Hz, 1 H), 6.63 (s, 1 H), 3.83-3.90 (m, 4H), 3.20-3.26 (m, 4 H), 2.51 (s, 3 H). N-(3-(4- methylpiperazin-1-yl)phenyl)- 6-(o-tolyl)- 5H-pyrrolo[3,2- d]pyrimidin-2- amine

A4; [C₂₄H₂₆N₆ + H]⁺ 399.22; 399.2; 96.0% 0.057 g; (53%); yellow solid;TFA sdalt Sms: tert-butyl2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (72.8 mg,0.21 mol), K₂CO₃ (303 mg, 2.2 mmol), 3-(4-methylpiperazin-1-yl)aniline(69 mg, 0.36 mmol), Pd(OAc)₂ (5.7 mg, 0.025 mmol), dioxane (5 mL),Xantphos (29.5 mg, 0.051 mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.74 (s, 1H), 7.58 (d, J = 7.30 Hz, 1 H), 7.30-7.50 (m, 5 H), 7.25 (d, J = 7.80Hz, 1 H), 6.91 (dd, J = 8.30, 2.30 Hz, 1 H), 6.68 (s, 1 H), 3.85-3.99(m, 2 H), 3.57-3.70 (m, 2 H), 3.23-3.36 (m, 2 H), 3.07-3.21 (m, 2 H),2.99 (s, 3 H), 2.52 (s, 3 H). 2-(4-(2-methyl- 6-((6- (o-tolyl)-5H-pyrrolo[3,2- d]pyrimidin-2- yl)amino)pyrimidin- 4-yl)piperazin-1-yl)ethanol

A5; [C₂₄H₂₈N₈O + H]⁺ 445.24; 445.3; >99.6% 0.068 g; (65.0%); pale yellowsolid; 2HCl salt Sms: tert-butyl2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (72.5 mg,0.20 mol), K₂CO₃ (280 mg, 2.2 mmol),2-(4-(6-amino-2-methylpyrimidin-4-yl)piperazin-1- yl)ethanol (82 mg,0.34 mmol), Pd(OAc)₂ (5.0 mg, 0.022 mmol), dioxane (5 mL), Xantphos(23.5 mg, 0.041 mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.83 (s, 1 H), 7.57(d, J = 7.30 Hz, 1 H), 7.33-7.46 (m, 2 H), 6.78 (s, 1 H), 6.32 (s, 1 H),4.62-4.83 (br.m, 2 H), 3.93-4.00 (m, 2 H), 3.76-3.86 (br.m, 2 H),3.53-3.69 (br.m, 2 H), 3.37-3.43 (m, 2 H), 2,75 (s, 3 H), 2.52 (s, 3 H).2H obscured by the peaks due to the NMR solvent. 6-(2,6-dimethylphenyl)- N-(3-(4- methylpiperazin-1- yl)phenyl)-5H- pyrrolo[3,2-d]pyrimidin-2- amine

A6; [C₂₅H₂₈N₆ + H]⁺ 413.25; 413.3; 96.2% 32 mg, (22%) light brown solid;HCl salt Sms:2-chloro-6-(2,6-dimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidine (82 mg, 0.32mmol), 3- (4-methylpiperazin-1-yl)aniline (73 mg, 0.38 mmol), Pd(OAc)₂(11 mg, 0.016 mmol), Xantphos (74 mg, 0.13 mmol), K₂CO₃ (132 mg, 0.96mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.79 (s, 1 H), 7.35-7.43 (m, 1 H),7.27-7.35 (m, 2 H), 7.20 (d, J = 7.28 Hz, 2 H), 7.11-7.17 (m, 1 H),6.94-7.01 (m, 1 H), 6.48 (s, 1 H), 3.83-4.00 (m, 2 H), 3.56-3.69 (m, 2H), 3.21-3.28 (m, 2 H), 3.08-3.20 (m, 2 H), 2.98 (s, 3 H), 2.18 (s, 6 H)N-(3- (morpholino- methyl)phenyl)- 6-(o-tolyl)- 5H-pyrrolo[3,2-d]pyrimidin-2-amine

A7; [C₂₄H₂₅N₅O + H]⁺ 400.21; 400.2; 99.2% 0.086 g; (70%); light yellowsolid; TFA salt SMs: tert-butyl2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (82.6 mg,0.24 mol), K₂CO₃ (332 mg, 2.4 mmol), 3-(morpholinomethyl)aniline (76 mg,0.39 mmol), Pd(OAc)₂ (6.1 mg, 0.027 mmol), dioxane (5 mL), Xantphos(32.2 mg, 0.056 mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.74 (s, 1 H), 7.97(s, 1 H), 7.83 (d, J = 8.00 Hz, 1 H), 7.58 (d, J = 7.50 Hz, 1 H), 7.53(t, J = 8.00 Hz, 1 H), 7.36-7.49 (m, 3 H), 7.28 (d, J = 8.00 Hz, 1 H),6.69 (s, 1 H), 4.42 (s, 2 H), 3.77-4.12 (br.m, 4 H), 3.34-3.44 (br.m, 4H), 2.53 (s, 3 H). N-(4- morpholino- phenyl)-6- (o-tolyl)-5H-pyrrolo[3,2- d]pyrimidin-2- amine

A8; [C₂₃H₂₃N₅O + H]⁺ 386.19; 386.3; 97.8% 0.029 g; (33%); light orangesolid; TFA salt SMs (method: tert-butyl2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (60.5 mg,0.18 mol), K₂CO₃ (243 mg, 1.8 mmol), 4-morpholinoaniline (47 mg, 0.26mmol), Pd(OAc)₂ (4.0 mg, 0.018 mmol), dioxane (5 mL), Xantphos (20.4 mg,0.035 mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.73 (s, 1 H), 7.55 (d, J =7.78 Hz, 1 H), 7.34-7.49 (m, 5 H), 7.14 (d, J = 8.78 Hz, 2 H), 6.58 (s,1 H), 3.82-3.93 (m, 4 H), 3.18-3.27 (m, 4 H), 2.50 (s, 3 H) N-(3-((4-methylpiperazin-1- yl)methyl)phenyl)- 6-(o-tolyl)-5H- pyrrolo[3,2-d]pyrimidin-2-amine

A9; [C₂₅H₂₈N₆ + H]⁺ 413.24; 413.3; 98.8% 0.015 g (14%); pale yellowsolid; TFA salt SMs: tert-butyl2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (70 mg, 0.20mol), K₂CO₃ (283 mg, 2.0 mmol),3-((4-methylpiperazin-1-yl)methyl)aniline*2HCl (85.6 mg, 0.30 mmol),Pd(OAc)₂ (11.4 mg, 0.051 mmol), dioxane (5 mL), Xantphos (58.1 mg, 0.10mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 9.10 (s, 1 H), 7.90-7.98 (m, 2 H),7.85 (d, J = 8.78 Hz, 1 H), 7.59-7.77 (m, 4 H), 7.51 (d, J = 8.28 Hz, 1H), 6.90 (s, 1 H), 3.91 (s, 2 H), 3.24-3.46 (m, 4 H), 2.81-3.08 (m, 4H), 2.87 (s, 3 H), 2.47 (s, 3 H). 6-cyclopentyl- N-(3-(4-methylpiperazin-1- yl)phenyl)-5H- pyrrolo[3,2- d]pyrimidin-2- amine

A10; [C₂₂H₂₈N₆ + H]⁺ 377.25; 377.3; 96.0% 10.3 mg (7%); yellow solid;HCl salt Sms: 2-chloro-6-cyclopentyl-5H-pyrrolo[3,2-d]pyrimidine (82 mg,0.37 mmol), 3-(4- methylpiperazin-1-yl)aniline (85 mg, 0.44 mmol),Pd(OAc)₂ (12.5 mg, 0.019 mmol), Xantphos (86 mg, 0.15 mmol), K₂CO₃ (153mg, 1.1 mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.58 (s, 1 H), 7.31-7.42(m, 1 H), 7.27 (br. s., 1 H), 7.06-7.15 (m, 1 H), 6.91-6.98 (m, 1 H),6.38 (s, 1 H), 3.84-3.95 (m, 2 H), 3.56-3.69 (m, 2 H), 3.23-3.30 (m, 2H), 3.03-3.17 (m, 2 H), 2.98 (s, 3 H), 2.13-2.30 (m, 3 H), 1.70- 1.93(m, 6 H) N-(3-(4- methylpiperazin-1- yl)phenyl)-6- (thiophen-3-yl)-5H-pyrrolo[3,2- d]pyrimidin-2- amine

A11; [C₂₁H₂₂N₆S + H]⁺ 391.16; 391.2; 98.7% 43 mg (19%); orange solid;HCl salt Sms: 2-chloro-6-(thiophen-3-yl)-5H-pyrrolo[3,2-d]pyrimidine(128 mg, 0.54 mmol), 3-(4- methylpiperazin-1-yl)aniline (125 mg, 0.65mmol), Pd(OAc)₂ (18 mg, 0.027), Xantphos (125 mg, 0.22 mmol), K₂CO₃ (224mg, 1.6 mmol) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.65 (s, 1 H), 8.19-8.24 (m,1 H), 7.65-7.71 (m, 2 H), 7.35-7.41 (m, 1 H), 7.26-7.31 (m, 1 H), 7.13(d, J = 9.03 Hz, 1 H), 6.96 (d, J = 9.29 Hz, 1 H), 6.84 (s, 1 H),3.87-3.97 (m, 2 H), 3.60-3.68 (m, 2 H), 3.25-3.30 (m, 2 H), 3.08-3.20(m, 2 H) 2.98 (s, 3 H) 6-(2,6- dimethylphenyl)- N-(3- morpholinophenyl)-5H-pyrrolo[3,2- d ]pyrimidin-2- amine

A12; [C₂₄H₂₅N₅O + H]⁺ 400.22; 400.3; 99.9% 38 mg (9%); light orangesolid; HCl salt Sms:2-chloro-6-(2,6-dimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidine (92 mg, 0.36mmol), 3- morpholinoaniline (76 mg, 0.43 mmol), Pd(OAc)₂ 8 mg, 0.036mmol), Xantphos (83 mg, 0.14 mmol), K₂CO₃ (149 mg, 1.1 mmol) ¹H NMR (400MHz, CD₃OD) δ ppm 8.83 (s, 1 H), 7.91-7.98 (m, 1 H) 7.53-7.60 (m, 1 H),7.45-7.51 (m, 1 H), 7.28-7.37 (m, 2 H), 7.17-7.25 (m, 2 H), 6.53-6.59(m, 1 H), 3.99- 4.09 (m, 4 H), 3.52-3.64 (m, 4 H), 2.19 (s, 6 H)6-(2-fluorophenyl)- N-(3-morpholino- phenyl)- 5H-pyrrolo[3,2-d]pyrimidin-2- amine

A13; [C₂₂H₂₀FN₅O + H]⁺ 390.18; 390.3; 97.4% 47 mg (11%); yellow solid;HCl salt Sms: 2-chloro-6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine(247 mg, 1.0 mmol), 3- morpholinoaniline (214 mg, 1.2 mmol), Pd(OAc)₂(22 mg, 0.10 mmol), Xantphos (231 mg, 0.40 mmol), K₂CO₃ (414 mg, 3.0mmol) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.82 (s, 1 H), 7.94-8.00 (m, 1 H),7.72-7.78 (m, 1 H), 7.58-7.66 (m, 1 H), 7.49-7.56 (m, 1 H), 7.33-7.46(m, 3 H), 7.22-7.28 (m, 1 H), 7.01 (s, 1 H), 3.96-4.03 (m, 4 H),3.46-3.55 (m, 4 H) N-(3- morpholino- phenyl)-6- (tetrahydro-2H-pyran-4-yl)- 5H-pyrrolo[3,2-d] pyrimidin-2-amine

A14; [C₂₁H₂₅N₅O₂ + H]⁺ 380.21; 380.3; >99.8% 52 mg (10%); beige solid;HCl salt SMs:2-chloro-6-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[3,2-d]pyrimidine (300mg, 1.3 mmol), 3-morpholinoaniline 270 mg, 1.5 mmol), Pd(OAc)₂ (28 mg,0.13 mmol), Xantphos (147 mg, 0.25 mmol), K₂CO₃ (526 mg, 3.8 mmol) ¹HNMR (400 MHz, CD₃OD) δ ppm 8.69 (s, 1 H), 7.95-8.04 (m, 1 H), 7.46-7.61(m, 2 H), 7.30-7.39 (m, 1 H), 6.51 (s, 1 H), 4.06 (br. s, 6 H), 3.61(br. s., 6 H), 3.19-3.27 (m, 1 H), 1.95-2.05 (m, 2 H), 1.82-1.95 (m, 2H) N-(4- (morpholino- methyl) phenyl)-6-(o-tolyl)- 5H-pyrrolo[3,2-d]pyrimidin-2-amine

A15; [C₂₄H₂₅N₅O + H]⁺ 399.21; 400.22; 400.3; >99.8% 78 mg (18%); orangesolid; HCl salt SMs: 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine(243 mg, 1.0 mmol), 4- (morpholinomethyl)aniline (230 mg, 1.2 mmol),Pd(OAc)₂ (22.4 mg, 0.10 mmol), Xantphos (116 mg, 0.20 mmol), K₂CO₃ (414mg, 3.0 mmol) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.80 (s, 1 H), 7.96 (br. s.,1 H), 7.74 (d, J = 8.03 Hz, 1 H), 7.54-7.64 (m, 2 H), 7.33-7.51 (m, 4H), 6.75 (s, 1 H), 4.44 (s, 2 H), 3.98-4.13 (m, 2 H), 3.74-3.90 (m, 2H), 3.38-3.50 (m, 2 H), 3.21-3.28 (m, 2 H), 2.52 (s, 3 H)2-(4-(3-((6-(2- chlorophenyl)-5H- pyrrolo[3,2- d]pyrimidin-2-yl)amino)phenyl) piperazin-1-yl) ethanol

A16; [C₂₄H₂₅ClN₆O + H]⁺ 449.18; 449.3; 98.8% 10 mg (11%); pale yellowsolid; HCl salt Sms:2-chloro-6-(2-chlorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (50 mg, 0.19mol), K₂CO₃ (260 mg, 1.9 mmol),2-(4-(3-aminophenyl)piperazin-1-yl)ethanol (63 mg, 0.28 mmol), Pd(OAc)₂(4.2 mg, 0.019 mmol), dioxane (5 mL), Xantphos (21.9 mg, 0.038 mmol). ¹HNMR (400 MHz, CD₃OD) δ ppm 8.87 (s, 1 H), 7.76 (dd, J = 6.53, 2.50 Hz, 1H), 7.67 (dd, J = 7.30, 1.60 Hz, 1 H), 7.51-7.61 (m, 2 H), 7.41 (t, J =8.03 Hz, 1 H), 7.30 (br. s., 1 H), 7.15 (d, J = 7.78 Hz, 1 H), 7.00 (dd,J = 7.15, 0.63 Hz, 1 H), 6.89 (s, 1 H), 3.87-4.00 (m, 3 H), 3.72- 3.81(m, 1 H), 3.47-3.55 (m, 2 H), 3.34-3.45 (m, 4 H), 3.18-3.29 (m, 2 H).N-(4-(4- methylpiperazin-1- yl)phenyl)-6- (o-tolyl)- 5H-pyrrolo[3,2-d]pyrimidin-2- amine

A17; [C₂₄H₂₆N₆ + H]⁺ 399.23; 399.3; 95.5% 78 mg (18%); yellow solid; HClsalt Sms: 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine (243 mg, 1.0mmol), 4-(4- methylpiperazin-1-yl)aniline (229 mg, 1.2 mmol), Pd(OAc)₂(22.4 mg, 0.10 mmol), Xantphos (116 mg, 0.20 mmol), K₂CO₃ (414 mg, 3.0mmol) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.73 (s, 1 H), 7.55 (d, J = 8.03 Hz,1 H), 7.48 (d, J = 8.53 Hz, 2 H), 7.33-7.46 (m, 3 H), 7.16 (d, J = 8.53Hz, 2 H), 6.60 (s, 1 H), 3.86-3.94 (m, 2 H), 3.61-3.68 (m, 2 H),3.07-3.18 (m, 2 H), 2.99 (s, 3 H), 2.49 (s, 3 H), signal due to 2Hburied under the solvent peak at 3.31 ppm. N-(4-((4- methylpiperazin-1-yl)methyl)phenyl)- 6-(o-tolyl)-5H- pyrrolo[3,2-d] pyrimidin-2-amine

A18; [C₂₅H₂₈N₆ + H]⁺ 413.24; 413.4; 97.9% 162 mg (36%); yellow solid;HCl salt SMs: 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine (243 mg,1.0 mmol), 4-((4- methylpiperazin-1-yl)methyl)aniline (246 mg, 1.2mmol), Pd(OAc)₂ (22.4 mg, 0.10 mmol), Xantphos (116 mg, 0.20 mmol),K₂CO₃ (414 mg, 3.0 mmol) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.79 (s, 1 H),7.81 (d, J = 8.03 Hz, 2 H), 7.68 (d, J = 8.78 Hz, 2 H), 7.59 (d, J =7.78 Hz, 1 H), 7.36-7.50 (m, 3 H), 6.74 (s, 1 H), 4.45 (br. s., 2 H),3.40- 3.87 (m, 8 H), 3.02 (s, 3 H), 2.52 (s, 3 H) N-(3-morpholinopropyl)- 6-(o-tolyl)-5H- pyrrolo[3,2- d]pyrimidin-2- amine

A19; [C20H₂₅N₅O + H]⁺ 352.2; 352.3; 96.9% 35 mg (43%); pale yellowsolid; HCl salt Sms: 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine(50 mg, 0.21 mmol), 3- morpholinopropan-1-amine (178 mg, 1.23 mmol), 4 MHCl in dioxane (0.10 mL) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.72 (1 H, s),7.55 (d, J = 8.03 Hz, 1 H), 7.34-7.48 (m, 3 H), 6.61 (s, 1 H), 4.01-4.11(m, 2 H), 3.76-3.87 (m, 2 H), 3.63-3.73 (m, 2 H), 3.49- 3.58 (m, 2 H),3.26-3.31 (m, 2 H), 3.10-3.24 (m, 2 H), 2.49 (s, 3 H), 2.13-2.26 (m, 2H) 6-(2-chloro- phenyl)-N- (3-morpholino- phenyl)- 5H-pyrrolo[3,2-d]pyrimidin-2- amine

A20; [C₂₂H₂₀ClN₅O + H]⁺ 406.14; 406.3; 98.1%; 5.2 mg (3%); off whitesolid; free base Sms:2-chloro-6-(2-chlorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (120 mg, 0.45mol), K₂CO₃ (410 mg, 3.0 mmol), 3-morpholinoaniline (129 mg, 0.72 mmol),Pd(OAc)₂ (10 mg, 0.044 mmol), dioxane (20 mL), Xantphos (54 mg, 0.093mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.61 (s, 1 H), 7.68-7.73 (m, 1 H),7.58-7.63 (m, 1 H), 7.44-7.48 (m, 2 H), 7.42 (s, 1 H), 7.14-7.25 (m, 2H), 6.70 (s, 1 H), 6.63 (d, J = 7.30 Hz, 1 H), 3.83-3.90 (m, 4 H),3.14-3.21 (m, 4 H). (1r,4)-4-((6- (o-tolyl)- 5H-pyrrolo[3,2-d]pyrimidin-2- yl)amino) cyclohexanol

A21; [C₁₉H₂₂N₄O + H]⁺ 323.19; 323.3; 98.0% 25 mg (37%); white solid;free base Sms: 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine (50 mg,0.21 mmol), trans-4- aminohexanol (145 mg, 1.3 mmol), 4 M HCl in dioxane(0.10 mL) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.30 (br. s., 1 H), 8.40 (s,1 H), 7.47-7.54 (m, 1 H), 7.28-7.39 (m, 3 H), 6.35 (s, 1 H), 6.07 (d, J= 7.53 Hz, 1 H), 4.49-4.56 (m, 1 H), 3.60-3.73 (m, 1 H), 3.36-3.46 (m, 1H), 2.44 (s, 3 H), 1.88-1.98 (m, 2 H), 1.77-1.87 (m, 2 H), 1.20- 1.29(m, 4 H) (1s,4s)-4-((6- (o-tolyl)- 5H-pyrrolo[3,2- d]pyrimidin-2-yl)amino) cyclohexanol

A22; [C₁₉H₂₂N₄O + H]⁺ 323.19; 323.3; 96.8% 11.1 mg (16%); white solid;free base SMs: 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine (50 mg,0.21 mmol), cis-4- aminohexanol (145 mg, 1.3 mmol), 4 M HCl in dioxane(0.10 mL) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.30 (s, 1 H), 8.41 (s, 1 H),7.46-7.54 (m, 1 H), 7.26-7.40 (m, 3 H), 6.34 (s, 1 H), 6.06 (d, J = 7.78Hz, 1 H), 4.29-4.36 (m, 1 H), 3.68-3.81 (m, 2 H), 2.44 (s, 3 H),1.44-1.74 (m, 8 H) N-(tetrahydro-2H- pyran-4-yl)-6-(o- tolyl)-5H-pyrrolo[3,2- d]pyrimidin-2- amine

A23; [C₁₈H₂₀N₄O + H]⁺ 309.17; 309.3; 98.0% 14.1 mg (22%); white solid;free base SMs: 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine (50 mg,0.21 mmol), 4- aminotetrahydropyran (127 mg, 1.3 mmol), 4 M HCl indioxane (0.10 mL) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.42 (s, 1 H), 7.50 (d,J = 7.28 Hz, 1 H), 7.25-7.38 (m, 3 H), 6.36 (s, 1 H), 3.94-4.08 (m, 3H), 3.52-3.63 (m, 2 H), 2.47 (s, 3 H), 1.98-2.08 (m, 2 H), 1.50-1.67 (m,2 H) N-((tetrahydro- 2H-pyran-4-yl) methyl)-6- (o-tolyl)-5H-pyrrolo[3,2- d]pyrimidin-2- amine

A24; [C₁₉H₂₂N₄O + H]⁺ 323.19; 323.3; 98.9% 16.5 mg (32%); white solid;free base SMs: 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine (40 mg,0.21 mmol), (tetrahydro-2H- pyran-4-yl)methanamine (113 mg, 0.99 mmol),4 M HCl in dioxane (0.080 mL) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.41 (s, 1H), 7.50 (d, J = 7.53 Hz, 1 H), 7.26-7.38 (m, 3 H), 6.36 (s, 1 H),3.91-4.00 (m, 2 H), 3.37-3.47 (m, 2 H), 2.47 (s, 3 H), 1.88-2.01 (m, 1H), 1.71-1.80 (m, 2 H), 1.28-1.42 (m, 2 H). signal due to 2H buriedunder the solvent peak at 3.31 ppm. 6-(2-methoxy- phenyl)- N-(3-morpholino- phenyl)- 5H-pyrrolo[3,2-d] pyrimidin-2-amine

A35; [C₂₃H₂₃N₅O₂ + H]⁺ 402.2; 402.3; 96.5% 43 mg (52%); orange solid;HCl salt Sms: 2-chloro-6-(2-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine(50 mg, 0.19 mmol), 3- morpholinoaniline (137 mg, 0.77 mmol), 4 M HCl indioxane (0.10 mL) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.73 (s, 1 H), 7.92-7.99(m, 1 H), 7.68-7.75 (m, 1 H), 7.54-7.61 (m, 1 H), 7.47-7.54 (m, 1 H),7.26-7.37 (m, 2 H), 7.14-7.23 (m, 2 H), 7.02 (s, 1 H), 4.09 (s, 3 H),3.95-4.02 (m, 4 H), 3.44-3.52 (m, 4 H) N-((1- morpholino- cyclopentyl)methyl)-6- (o-tolyl)- 5H-pyrrolo[3,2- d]pyrimidin-2- amine

A36; [C₂₃H₂₉N₅O + H]⁺ 392.25; 392.4; 96.0% 44 mg (52%); beige solid; HClsalt SMs: 2-chloro-6-(o-tolyl)-5H-pyrrolo[3,2-d]pyrimidine (50 mg, 0.20mmol), (1- morpholinocyclopentyl)methanamine (151 mg, 0.82 mmol), 4 MHCl in dioxane (0.10 mL) ¹H NMR (400 MHz, CD₃OD) δ ppm 8.74 (br. s., 1H), 7.57 (d, J = 7.28 Hz, 1 H), 7.33-7.51 (m, 3 H), 6.68 (s, 1 H),4.01-4.18 (m, 4 H), 3.83-3.97 (m, 2 H), 3.62-3.77 (m, 2 H), 3.44- 3.58(m, 2 H), 2.51 (s, 3 H), 2.02-2.20 (m, 4 H), 1.81-1.99 (m, 4 H)

Example B: RIPK2 Inhibition Assay

Active RIPK2 was purchased from Life Technologies as His-tagged ofcatalityc domain (amin acids 1-299) of human RIPK2 kinase expressed ininsect cells. Amino terminal 6 histidine, sumo tagged human TTK(residues 1-275) was expressed in E. coli, and purified to >95%homogeneity by Ni²⁺ agarose, gel filtration, and ion exchangechromatography.

RIPK2 activity was measured using an indirect ELISA detection system.His—RIPK2 (0.6 nM) was incubated in the presence of 6 μM ATP (Sigma cat# A7699), 20 mM Hepes, pH 7.5, 1 mM EGTA, 2.5 mM MgCl₂, 2.5 mM MnCl₂ and0.01% Triton X-100 in a 96 well microtitre plate pre-coated with aminoterminal 6 histidine, sumo tagged TTK (amino acid residues 1-275). Thereaction was allowed to proceed for 30 minutes, followed by 5 washes ofthe plate with Wash Buffer (phosphate buffered saline supplemented with0.2% Tween 20), and incubation for 30 minutes with a 1:3000 dilution ofprimary antibody (Cell Signaling cat #9381). The plate was washed 5times with Wash Buffer, incubated for 30 minutes in the presence ofsecondary antibody coupled to horse radish peroxidase (BioRad cat#1721019, 1:3000 concentration), washed an additional 5 times with WashBuffer, and incubated in the presence of TMB substrate (Sigma cat #T0440). The colorimetric reaction was allowed to continue for 5 minutes,followed by addition of stop solution (0.5 N H₂SO₄), and quantified bydetection at 450 nm with either a monoChromatic or filter based platereader (Molecular Devices M5 or Beckman DTX880, respectively).

Compound inhibition was determined at either a fixed concentration (10μM) or at a variable inhibitor concentration (typically 50 μM to 0.1 μMin a 10 point dose response titration). Compounds were pre-incubated inthe presence of enzyme for 15 minutes prior to addition of ATP and theactivity remaining quantified using the above described activity assay.The % Inhibition of a compound was determined using the followingformula; % Inhibition=100×(1−(experimental value−background value)/(highactivity control−background value)). The IC₅₀ value was determined usinga non-linear 4 point logistic curve fit (XLfit4, IDBS) with the formula;(A+(B/(1+((x/C)^D)))), where A=background value, B=range, C=inflectionpoint, D=curve fit parameter.

In Table 1 presents IC₅₀ value ranges for compound examples indicated as“A,” “B,” and “C,” for values less than or equal to 0.1 μM; thosegreater than 0.1 μM and less than or equal to 0.5 μM; and those greaterthan 0.5 μM, respectively.

TABLE 1 In vitro activity against RIPK2 data for the example compoundsof the invention. Example RIPK2 IC₅₀ range A1 C A2 A A3 A A4 A A5 C A6 AA7 A A8 A A9 A A10 C A11 A A12 A A13 B A14 C A15 A A16 A A17 A A18 A A19C A20 A A21 B A22 C A23 C A24 B A25 B A26 C

Example C: Activity Against Cancer Cell Line for Example Compounds ofthe Invention

Breast cancer cells (MDA-MB-231 and MDA-MB-468), colon cancer cells(HCT116 and HT-29) and ovarian cancer cells (SKOV-3 and OVCAR-3) wereseeded (1000 to 4000 in 80 μL per well depending on the cell growthrate) into 96 well plates 24 hours before compound overlay. Compoundswere prepared as 10 mM stock solutions in 100% DMSO which were dilutedwith DMEM (Dulbecco's Modified Eagle's Medium) cell growth Medium(Invitrogen, Burlington, ON, Canada) containing 10% FBS (Fetal BovineSerum) to concentrations ranging from 50 nM to 250 μM. Aliquots (20 μL)from each concentration were overlaid to 80 μL of the pre-seeded cellsin the 96 well plates to make final concentrations of 10 nM to 50 μM.The cells were cultured for 5 days before the Sulforhodamine B assay(SRB) was performed to determine the compound's cell growth inhibitionactivity.

The cells are fixed in situ by gently aspirating off the culture mediaand adding 50 μL ice cold 10% trichloroacetic acid per well and incubateat 4° C. for 30-60 min. The plates are washed with H₂O five times andallowed to air dry for 5 min. Addition of 50 μL 0.4% (w/v) SRB solutionin 1% (v/v) acetic acid to each well and incubation for 30 min at rtcompletes the staining reaction. Following staining, plates are washedfour times with 1% acetic acid to remove unbound dye and then allowed toair dry for 5 min. The stain is solubilized with 100 μL of 10 mM Tris pH10.5 per well. Absorbance is read at 570 nm. The percentage (%) ofrelative growth inhibition was calculated by comparing to DMSO treatedonly cells (100%). GI₅₀'s were determined for compounds with cytotoxicactivity. The GI₅₀ was calculated using GraphPad PRISM software(GraphPad Software, Inc., San Diego, Calif., USA). GI₅₀ (growthinhibition) is the compound concentration that causes 50% inhibition ofcell growth.

In Table 2 lists GI₅₀ value ranges for compound examples against breastcancer cell lines (MDA-MB-231, MDA-MB-468), colon cancer cell lines(HCT116, HT-29) and ovarian cancer cell lines (OVCAR-3, SKOV-3) aregiven. The example compounds demonstrated varying growth inhibition/cellkilling activity against cells of breast cancer, colon cancer, andovarian cancer. The GI₅₀ ranges are indicated as “A,” “B,” and “C,” forvalues less than or equal to 1 μM; those greater than 1 μM and less thanor equal to 10 μM; and those greater than 10 μM, respectively.

TABLE 2 In vitro cell antiproliferative activity data for ExampleCompounds of the Invention Breast GI₅₀ range Colon GI₅₀ range OvarianGI₅₀ range Example MDA-MB-231 MDA-MB-468 HCT116 HT29 OVCAR-3 SKOV-3 A3 AA A A A A A8 C ND C C C C A12 B B B B A A A13 A A A A A A A7 B ND B B BB A2 B B B B B B A4 A A A A A B A6 B ND B A A A A9 C ND B A A A

Example D: In Vivo Response of HCT116 Xenografts to Treatment withExemplified Compounds of the Invention

HCT116 colon cancer cells were purchased from ATCC (American TypeCulture Collections) and cultured in DMEM (Dulbecco's Modified eaglemedium-purchased from GIBCO) supplemented with 10% fetal calf serum.Five million cells were injected subcutaneously in the right flank of6-8 week old male CB-17 SCID mice. When the mean tumor volume reached80-120 mm³, mice were randomized into 5 groups (n=5) and received eithervehicle (10% NMP, 40% PEG, 50% H₂O) or compound at the doses indicated.

Tumor volume and body weight were measured three times weekly. Tumorvolume was calculated by the following formula: x²y/2. Percent tumorgrowth inhibition after initiation of treatment with compound wascalculated by: TGI=100×1−(tumor volume_(final)−tumor volume_(initial)for compound treated group)/(tumor volume_(final)−tumor volume_(initial)for compound control group).

Test results are shown in FIG. 1.

Example E: Effect of Example A3 on Cytokine Production by DendriticCells

IL-12-yellow fluorescent protein (YFP) reporter mouse bone marrowdendritic cells were stimulated for 24 hours with 0.3 ng/ml LPS±1 μg/mlMDP (i.e., NOD2 agonist) in the presence of Example A3 (FIG. 2A).IL-12-yellow fluorescent protein (YFP) reporter mouse bone marrowdendritic cells were stimulated for 24 hours with 0.3 μg/ml Pam3Cys±1μg/ml MDP (i.e., NOD2 agonist) in the presence of Example A3 (FIG. 2B).Flow cytometric analysis showed that Example A3 caused a dose-dependentreduction in the mean fluorescence intensity YFP (i.e., the amount ofIL-12; left panels). This effect of Example A3 was MDP-dependent andsuggests that it involves blocking NOD2-RIPK2 responses. Example A3 hada minimal effect on the percentage of YFP positive cells (i.e., thepercentage of IL-12 positive cells; middle panels), and no measurableeffect on cell viability as assessed by 7AAD exclusion (right panels).Data are represented as the mean±SEM of triplicate measurements. Levelsof IL-12 p70 (FIG. 2C, left panel) and TNFα (FIG. 2C, right panel) inthe cell culture supernatants from A were measured by ELISA techniqueswith commercially available kits. Example A3 caused a dose-dependentreduction in the levels of both cytokines. Data are represented as themean±SEM of triplicate measurements.

What is claimed is:
 1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Cy iscycloaliphatic, heterocyclyl, aryl, or heteroaryl; Y is absent,—CR^(b)R^(b)—, —O—, —NR^(b)—, —S(O)_(n)—; R₁ is cycloaliphatic,heterocyclyl, aryl or heteroaryl, each of which is optionallysubstituted with 1 to 3 groups individually represented by R^(a); R₃ isH, heterocyclyl or heteroaryl optionally substituted with 1 to 3 groupsselected from —F, —Cl, —Br, I, —CN, —NO₂, —OR^(b), —C₁-C₄alkyl,—(C₁-C₃)alkylene-OR^(b), —(C₁-C₃)alkylene-NR^(b)R^(b), —C₁-C₄haloalkyl,—C₁-C₄haloalkoxy, (C₃-C₈)cycloalkyl, —NR^(b)R^(b), —C(═O)NR^(b)R^(b),—NR^(b)(C═O)NR^(b)R^(b), —S(O)_(n)NR^(b)R^(b), C(═O)OR^(b),—OC(═O)OR^(b), —S(O)_(n)R^(b), —NR^(b)S(O)_(n)R^(b), —C(═S)OR^(b),—O(C═S)R^(b), —NR^(b)C(═O)R^(b), —C(═S)NR^(b)R^(b), —NR^(b)C(═S)R^(b),—NR^(b)(C═O)OR^(b), —O(C═O)NR^(b)R^(b), —NR^(b)(C═S)OR^(b),—O(C═S)NR^(b)R^(b), NR^(b)(C═S)NR^(b)R^(b), —C(═S)R^(b) or —C(═O)R^(b);each R₄ is independently selected from —F, —Cl, —Br, I, —CN,—NR^(b)R^(b), —OR^(b), —C₁-C₄alkyl, —(C₁-C₃)alkylene-OR^(b),—(C₁-C₃)alkylene-NR^(b)R^(b), —C₁-C₄haloalkyl, or —C₁-C₄haloalkoxy; eachR^(a) is independently selected from —F, —Cl, —Br, I, —CN, OR^(b),—C₁-C₄alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —C₁-C₄haloalkyl,—C₁-C₄haloalkoxy, —(C₁-C₃)alkylene-OR^(b), or—(C₁-C₃)alkylene-NR^(b)R^(b); each R^(b) is independently —H or—C₁-C₄alkyl; x is 0, 1, 2, 3, or 4; each m is independently 0, 1, 2, or3; and each n is independently 0, 1, or
 2. 2. The compound of claim 1,wherein the compound is represented by structural formula (II):

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim2, wherein the compound is represented by structural formula (III):

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim3, wherein R₁ is optionally substituted phenyl, optionally substitutedcyclopentyl, optionally substituted cyclohexyl, optionally substitutedthienyl, optionally substituted pyridinyl, optionally substitutedthiazolyl, optionally substituted pyrrolyl, optionally substitutedimidazolyl, optionally substituted furanyl, optionally substitutedoxazolyl, optionally substituted isoxazolyl, optionally substitutedpyrazolyl, optionally substituted isothiazolyl, optionally substitutedpyrmidinyl, optionally substituted pyrazinyl, optionally substitutedpyridazinyl, optionally substituted oxadiazolyl, optionally substitutedtetrahydropyranyl, optionally substituted triazolyl, or optionallysubstituted thiadiazolyl.
 5. The compound of claim 4, wherein R₁ isoptionally substituted phenyl, optionally substituted cyclopentyl,optionally substituted thienyl, or optionally substitutedtetrahydropyranyl.
 6. The compound of claim 5, wherein R₃ is optionallysubstituted monocylic heterocyclyl or optionally substituted monocylicheteroaryl.
 7. The compound of claim 6, wherein m is
 0. 8. The compoundof claim 7, wherein R₃ is optionally substituted azetidinyl, optionallysubstituted morpholinyl, optionally substituted piperazinyl, optionallysubstituted piperidinyl, optionally substituted tetrahydropyranyl,optionally substituted pyrrolidinyl, optionally B optionally substitutedthiomorpholinyl, optionally substituted tetrahydropyranyl, optionallysubstituted tetrahydrofuranyl, optionally substituted homomorpholinyl,optionally substituted homopiperazinyl, optionally substitutedthiomorpholine dioxide, or optionally substituted thiomorpholine oxide.9. The compound of claim 8, wherein R₃ is optionally substitutedmorpholinyl, optionally substituted piperazinyl, optionally substitutedpiperidinyl, or optionally substituted thiomorpholinyl.
 10. The compoundof claim 9, wherein the compound is represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof, wherein R₅ is —C₁-C₄alkylor —(C₁-C₃)alkylene-OR^(b).
 11. The compound of claim 9, wherein thecompound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein Y is absent or—CH₂—; and Y is attached to the meta or para position of the phenylring.
 12. The compound of claim 9, wherein the compound is representedby the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein R₅ is —H,C₁-C₄alkyl, —(C₁-C₃)alkylene-OR^(b); Y is absent or —CH₂—; and Y isattached to the meta or para position of the phenyl ring.
 13. Thecompound of claim 9, wherein R₁ is


14. The compound of claim 13, wherein each R^(a) is independentlyselected from —F, —Cl, or —CH₃.
 15. A pharmaceutical compositioncomprising a compound of claim 1 and a pharmaceutically acceptablecarrier or diluent.
 16. A compound or a pharmaceutically acceptable saltthereof, wherein the compound is